Submissions for variant NM_000059.4(BRCA2):c.9285C>G (p.Asp3095Glu)

dbSNP: rs80359198

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045779	SCV000073792	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 3095 of the BRCA2 protein (p.Asp3095Glu). This variant is present in population databases (rs80359198, gnomAD 0.0009%). This missense change has been observed in individual(s) with BRCA2-related conditions (PMID: 18451181, 18951446, 22678057). It has also been observed to segregate with disease in related individuals. This variant is also known as 9513C>G. ClinVar contains an entry for this variant (Variation ID: 52805). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 18451181, 22678057, 23108138). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000223197	SCV000276898	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-26	criteria provided, single submitter	clinical testing	The p.D3095E pathogenic mutation (also known as c.9285C>G), located in coding exon 24 of the BRCA2 gene, results from a C to G substitution at nucleotide position 9285. The aspartic acid at codon 3095 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been classified as a likely pathogenic alteration by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). The p.D3095E alteration was not able to perform complementation in mouse ES cell-based assays (Biswas K et al. Hum Mol Genet. 2012 Sep 15;21(18):3993-4006; Mesman RLS et al. Genet Med 2019 02;21(2):293-302). A homology-directed DNA repair (HDR) assay has demonstrated this variant to be non-functional (Guidugli L et al. Am J Hum Genet 2018 02;102(2):233-248; Hart SN et al. Genet Med, 2019 01;21:71-80; Richardson ME et al. Am J Hum Genet 2021 03;108(3):458-468).This alteration has been reported in multiple families with hereditary breast and ovarian cancer, including at least two families with a history of male breast cancer, as well as cohorts of prostate and pancreatic cancer patients (Biswas K et al. Hum Mol Genet. 2012 Sep 15;21(18):3993-4006; Gabaldo Barrios X et al. Fam. Cancer 2017 Oct;16(4):477-489; Antonarakis ES et al. Eur. Urol. 2018 08;74:218-225; Wong W et al. Cancer. 2019 05;125:1441-1448; Isaacsson Velho P et al. Prostate. 2018 04;78:401-407). Of note, this alteration is also designated as 9513C>G in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as a pathogenic mutation.
GeneDx	RCV000236007	SCV000292530	pathogenic	not provided	2023-08-10	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Plon et al., 2008; Gabald Barrios et al., 2017; Wong et al., 2019; Lotan et al., 2021); Published functional studies demonstrate a damaging effect: reduced homology-directed repair (HDR) activity, aberrant centriole amplification, failure to rescue lethality of Brca2 null ES cells (Farruguia et al., 2008; Biswas et al., 2012; Guidugli et al., 2013; Ikegami et al., 2020; Richardson et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 9513C>G; This variant is associated with the following publications: (PMID: 25085752, 29439820, 28277317, 30293905, 17924331, 22678057, 18451181, 21990134, 17899372, 19043619, 24323938, 18951446, 28477318, 25447315, 16875939, 21990165, 29394989, 29988080, 30787465, 32719484, 29884841, 29368341, 29922827, 32444794, 31948886, 33609447, 32906206, 33462368, 30620386, 35665744, 12228710, 23108138)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236007	SCV000600853	pathogenic	not provided	2023-01-21	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/250672 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 16875939 (2006), 28477318 (2017), 8640235 (1996)) and prostate cancer (PMID: 29983880 (2018), 29439820 (2018)). Published functional studies have shown that this variant results in a deleterious effect on BRCA2 protein function (PMID: 22678057 (2012), 29394989 (2018), 29988080 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging.
Color Diagnostics, LLC DBA Color Health	RCV000223197	SCV000684048	pathogenic	Hereditary cancer-predisposing syndrome	2020-02-07	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 3095 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant disrupts homology-directed DNA repair activity (PMID: 18451181, 23108138, 29884841) and fails to complement cell lethality phenotype induced by loss of BRCA2 in mouse embryonic stem cell-based assays (PMID: 24323938, 29988080). This variant has been reported in many individuals affected with breast cancer (PMID: 16875939, 18951446, 28477318, 30728895) and prostate cancer (PMID: 29368341, 29439820, 29983880, 30293905). In addition, several multifactorial likelihood models using health history, in silico, and experimental data have suggested this variant have a high probability of being pathogenic (PMID: 17924331, 19043619, 21990134, 25085752, 29394989). This variant has been identified in 1/250672 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045779	SCV000695233	pathogenic	Hereditary breast ovarian cancer syndrome	2021-12-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9285C>G (p.Asp3095Glu) results in a conservative amino acid change located in the 3rd oligonucleotide binding (OB) fold (IPR015188), which is part of the DNA-binding domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250672 control chromosomes (gnomAD). c.9285C>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Maillet_2006, Biswas_2012, Gabaldo_2017). Segregation data in HBOC families was suggestive, but not conclusive of causality (e.g. Biswas_2012). Multiple publications have reported experimental evidence evaluating an impact on protein function. In these functional studies the variant was shown to cause significantly reduced HDR activity, increased aberrant centriole amplification, and reduced cell viability in null-rescue survival assays (example: Farrugia_2008, Biswas_2012, Guidugli_2012, Hart_2018, Mesman_2018, Ikegami_2020). In addition, multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be (likely) pathogenic (Easton 2007, Karchin_2008, Lindor 2012, Guidugli_2018). Six ClinVar submitters have assessed this variant since 2014: one classified the variant as likely pathogenic and five as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV000045779	SCV001478279	pathogenic	Hereditary breast ovarian cancer syndrome	2018-10-10	criteria provided, single submitter	curation	Data used in classification: The frequency of this variant is 1/138,632 individuals (gnomAD) (PM2_mod). This variant is predicted deleterious on AlignGVGD (class: C35), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (13.74) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the BRCA2 Homology-Directed Repair Activity assay for the DNA Binding Domain (Guidugli et al Cancer Res 2013;73:265-275,Couch Lab), the variant has a probability of pathogenicity of 1.0 (PS3_strong). This variant is classified on ClinVar as pathogenic by accredited diagnostic USA laboratories Ambry Genetics and GeneDx (2018) (PP5_sup). This variant produces the same amino acid change as a variant with overall classification on ClinVar as pathogenic (c.9285C>A p.Asp3095Glu) (PS1_strong). Data not used in classification: There are additional reports of this variant in ClinVar (9), BIC (12), and BRCA2 LOVD (6).
Sema4, Sema4	RCV000223197	SCV002532020	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-24	criteria provided, single submitter	curation
Baylor Genetics	RCV003473431	SCV004211826	pathogenic	Familial cancer of breast	2024-02-19	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077467	SCV000109265	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2010-03-30	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077467	SCV000147600	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000045779	SCV000587995	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research