Submissions for variant NM_000059.4(BRCA2):c.8764A>G (p.Ser2922Gly)

gnomAD frequency: 0.00001  dbSNP: rs80359132

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031769	SCV001161625	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000712
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195383	SCV000073636	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000590809	SCV000210482	likely benign	not provided	2019-12-03	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26023681, 19043619, 31131967, 31294896)
Ambry Genetics	RCV000165036	SCV000215734	likely benign	Hereditary cancer-predisposing syndrome	2022-01-12	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.
Color Diagnostics, LLC DBA Color Health	RCV000165036	SCV000683997	likely benign	Hereditary cancer-predisposing syndrome	2020-08-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281726	SCV000695182	benign	not specified	2022-07-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8764A>G (p.Ser2922Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250484 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.8764A>G, has been reported in the literature in individuals affected with breast cancer (Foley_2015, Dorling_2021), but was also found in multiple healthy controls (Dorling_2021). Co-occurrences with other pathogenic BRCA2 variant have been reported (c.4478_4481delAAAG (p.Glu1493ValfsX10) in the BIC database and c.4127_4130delGAAA (p.Gly1376AlafsX11) in Foley_2015), providing supporting evidence for a benign role. In addition, a recent multifactorial likelihood analysis predicted this variant to be benign (Parsons_2019).To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (n=3), likely benign (n=3) / benign (n=2; including the expert panel). Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590809	SCV001133948	likely benign	not provided	2023-03-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000031769	SCV001139233	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031769	SCV004846066	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-10	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031769	SCV000054377	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2009-03-26	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031769	SCV000147457	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000045623	SCV000592229	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Ser2922Gly variant was identified in 1 of 516 proband chromosomes (frequency: 0.00193) from an individual with breast cancer (Foley_2015). The variant was also identified in a cohort of high-risk breast/ovarian cancer families, with the pathogenicity assessed to be inconclusive using the protein likelihood ratio model, a bioinformatics tool to predict whether a missense variant affects protein function (Karchin_2008). The variant was also identified in dbSNP (ID: rs80359132) as “With other allele”, ClinVar (with conflicting interpretations of pathogenicity (as likely benign by SCRP and as uncertain significance by Invitae, GeneDx, Ambry Geneticvs, COGR, and BIC)), Clinvitae (with conflicting interpretations of pathogenicity), COGR (as uncertain significance), Cosmic (as pathogenic, found in ovarian cancer ), LOVD 3.0 (2x as "inconclusive"), and the BIC Database (1x as "unknown clinical importance"). The variant was not identified in MutDB, UMD-LSDB, ARUP Laboratories, Zhejiang Colon Cancer Database. The variant was identified in control databases in 2 of 276204 chromosomes at a frequency of 0.000007 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 23950 chromosomes (freq: 0.000042), and European (Non-Finnish) in 1 of 125972 chromosomes (freq: 0.000008); but not observed in the Other, Latino, Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The p.Ser2922Gly residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.