Saturday, September 14, 2019

Informal Notes: Pathogenic Variant Risk for BRCA1/2 Mutations

[this set of notes branched out from this blog post

I think the estimates of 50% risk for breast cancer and 30% risk of ovarian cancer (in this infographic from the CDC) are in line with that I was expecting (although that doesn't capture mutations in BRCA1 being higher risk than BRCA2).  There is also this page with 60-75% risk for BRCA1 carriers and 50-70% risk for BRCA2 carriers (which I learned about from this Twitter reply).

Importantly, because of that Twitter communication, I read the book "Resurrection Lily" by Amy Byer Shainman.  I think this provides a very poignant perspective of what is like for yourself and/or your friends to go through either breast cancer treatment or prevention strategies (including up to preventive surgeries).  There are also multiple pages for risk estimates at the end of the book (pages 253 and 262-263 in my copy of the book).

Before I learned about that book, I think I would mostly typically refer to the Stanford BRCA Decision Tool (Kurian et al. 2012) that provides the variance of risk with a few options (although I'm not sure about the the intervals of screening, I don't know what is the relative effectiveness of hormonal therapies, and these estimates are at the gene level when I would expect some specific variants are higher risk than others).

While it is probably not going to be a problem in the future, there was a few days when the website was down.  So, I have attached some screenshots below (for BRCA1, and then BRCA2):

There was a recommendation for BRCA screening with a "B" grade in individuals with family histories, but a recommendation against BRCA screening with a "D" grade for individuals that didn't already have an increased risk of getting breast cancer (which I think is shown most clearly on the US Preventive Services website).  While the context is different, I think this figure from Biesecker 2019 shows one example of how filtering for prior risk may help (although not specifically for BRCA1/2).

While the topic of treatment strategies is a little different, I did notice some different number on an NCI Prevention Tweet (going back to topic of the range of risk estimates).  For example, that number seemed noticeably different for BRCA2, and the total risk reduction (particularly if you focus on death from breast cancer) also seemed different that the text in that Tweet (compared to what I see in the BRCA Decision Tool).

I also think I had another interesting conversation on Twitter here, some of which was converted into notes as a blog post (in terms of the overall prevalence of cancers where variants in moderate-to-high risk genes could be found).

There are some NCCN guidelines, although I thought those were more clear for criteria for screening versus recommendation for surgery in a BRCA-positive individual (which supports use on a "case-by-case basis").  Nevertheless, there is a lot of information available if you register for an account in this document, where some details for the "Bilateral Total Mastectomy" are on page MS-24.  Nevertheless, if this implies that people who don't qualify for the NCCN screening criteria (but had a test result, for some reason) are less likely to benefit from surgery, then perhaps that is helpful for making decisions.

The CDC has guidelines to define "average," "moderate," and "high" hereditary breast cancer risk.  I think their guidelines for genetic testing are similar to the NCCN and USPSTF (but you might find that website easier to read, and this page mentions that the USPSTF recommendations may affect health care coverage).  They also have an additional link for mammogram screenings that I didn't previously know about (on this page).

While I think there are some specific things that can be improved (for communication with non-scientists and communicating ranges for estimates of risk for specific variants, for example), I believe free, publicly-available resources like should play an important roles in helping patients learn more about their results.  ClinVar also provides some information, for variants in general.

For example, I believe these are the 3 BRCA1/BRCA2 variants covered by 23andMe: rs386833395rs80357906, and rs80359550.

The mutation described by the author of "Resurrection Lily" was referred to as "BRCA1 #5385 insC" as well as "BRCA1 #5382".  The book includes some references to ClinVar, but I don't believe I saw the rsID.  However, I believe those names refer to this variant in BRCA Exchange and this variant in ClinVar (based upon this Hamel et al. 2011 paper, and the synonyms in the database listings).  That makes this is second of the 3 variants tested by 23andMe above.

I am not sure about other available estimates.  However, there are selected genes with high (or highest?) lifetime risk variants for 7 cancer types (including breast and ovarian cancer) on this page from JScreen.

You can listen to some personal perspectives from a patient advocate in this podcast from DNA Today.  One statistic that caught my attention was that 1 in 40 Ashkenazi Jewish women have a mutation in the BRCA1 or BRCA2 genes.  I would also find that statistic on this page from the CDC.  I believe that page is combining pathogenic variants from the BRCA1 and BRCA2 genes when reporting "About 50 out of 100 women with a BRCA gene mutation will get breast cancer by the time they turn 70 years old".

There are also various ways to see the influence of ENIGMA on BRCA1 and BRCA2 variant annotations.  For example, BRCA Exchange includes pathogenic variant annotations from ENIGMA and ClinVar.  This page provides information for ENIGMA annotations in ClinVar, and there is also an ENIGMA BRCA1/BRCA2 expert panel in ClinGen (related to "Variant Pathogenicity" for BRCA1 and BRCA2).

Change Log:

9/14/2019 - public post date
11/12/2019 - add link to BRCA decision tool paper; website not currently working, but I will add some screenshots later (to show substantial difference in risk at the gene level for BRCA1 versus BRCA2)
11/20/2019 - add screenshots for BRCA Decision Tool.
12/2/2019 - add prior risk venn diagram link
7/6/2020 - add "breast cancer" label
8/16/2020 - add additional Penn/Basser link for risk estimates
8/22/2020 - add BRCAExchange link
10/25/2020 - add Resurrection Lily link
2/23/2022 - correct typo
12/1/2023 - add JScreen link (after listening to this podcast)
1/21/2024 - add additional DNA Today link as well as CDC Link for BRCA variants in women with Ashkenazi Jewish ancestry.
1/22/2024 - after receiving helpful feedback from GenomeConnect / ClinGen staff, add links for various types of ENIGMA annotations.

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