Submissions for variant NM_000059.4(BRCA2):c.9925G>A (p.Glu3309Lys)

gnomAD frequency: 0.00029  dbSNP: rs80359251

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080047	SCV000073929	likely benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130750	SCV000185641	likely benign	Hereditary cancer-predisposing syndrome	2018-06-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000195387	SCV000210521	likely benign	not provided	2020-11-27	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25451944, 24728327, 26689913, 28873162, 26295337, 26287763)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000195387	SCV000296744	likely benign	not provided	2022-11-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120378	SCV000695283	likely benign	not specified	2024-03-24	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9925G>A (p.Glu3309Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-05 in 282626 control chromosomes, predominantly at a frequency of 0.0008 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. The variant, c.9925G>A, has been reported in the literature in individuals affected with cancer, including breast cancer and lung adenocarcinoma (Pal_2015, Lu_2015, Mandelker_2017, Parry_2017, Ren_2021). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with a pathogenic variant has been observed at our laboratory (BRCA2 c.7110dupA , p.Ser2371fsX21; internal testing), providing supporting evidence for a benign role. c.9925G>A has been reported in the FLOSSIES database in 9 women older than age 70 years who have never had cancer, providing further supporting evidence for a benign role. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Ghosh_2015). The following publications have been ascertained in the context of this evaluation (PMID: 24728327, 25451944, 26689913, 28873162, 26287763, 28843361, 34196900). ClinVar contains an entry for this variant (Variation ID: 52918). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000130750	SCV000902904	likely benign	Hereditary cancer-predisposing syndrome	2015-11-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000112824	SCV001139279	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130750	SCV002532074	likely benign	Hereditary cancer-predisposing syndrome	2021-07-19	criteria provided, single submitter	curation
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000195387	SCV004847666	uncertain significance	not provided	2021-12-10	criteria provided, single submitter	clinical testing	The p.Glu3309Lys variant in BRCA2 has been reported in one individual with breast cancer and 2 individuals with other cancers (Pal 2015 PMID: 26287763, Parry 2017 PMID: 28843361, Mandelker 2017 PMID: 28873162). It has also been identified in 0.08% (20/24958) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BP4.
CeGaT Center for Human Genetics Tuebingen	RCV000195387	SCV005092803	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	BRCA2: BP4
ITMI	RCV000120378	SCV000084530	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112824	SCV000145732	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000112824	SCV000297582	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2009-12-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537218	SCV004743262	likely benign	BRCA2-related disorder	2020-10-16	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).