Submissions for variant NM_000059.4(BRCA2):c.8177A>G (p.Tyr2726Cys)

gnomAD frequency: 0.00001  dbSNP: rs80359064

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045442	SCV000073455	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2726 of the BRCA2 protein (p.Tyr2726Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer syndrome or prostate cancer (PMID: 25452441, 27495310, 28888541, 32875559). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52520). 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: 23108138, 29394989, 35736817). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV000130671	SCV000185557	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	The p.Y2726C variant (also known as c.8177A>G), located in coding exon 17 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8177. The tyrosine at codon 2726 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals with clinical histories suggestive of HBOC (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33(4):304-11; Jarhelle E et al. Fam. Cancer. 2017 Jan;16(1):1-16; Heramb C et al. Hered Cancer Clin Pract. 2018 Jan;16:3). In one study, this variant was analyzed using protein likelihood ratio, a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function, and was predicted to have a deleterious effect (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16). This variant was non-functional in a homology-directed DNA repair (HDR) assay (Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Hart SN et al. Genet. Med., 2019 01;21:71-80). Of note, this alteration is also designated as 8405A>G in published literature. Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Yang H et al. Science 2002 Sep;297:1837-48; Ambry Internal Data). As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000212271	SCV000210466	likely pathogenic	not provided	2023-02-28	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history of breast, ovarian, pancreatic, or other cancers (Couch et al., 2015; Jarhelle et al., 2016; O'Reilly et al., 2018); Published functional studies demonstrate a damaging effect: decreased homology-directed DNA break repair activity and inability to rescue cell lethality in a null cell line (Guidugli et al., 2013; Guidugli et al., 2018; Hart et al., 2019; Biswas et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8405A>G; This variant is associated with the following publications: (PMID: 24323938, 28888541, 19043619, 25452441, 23108138, 27495310, 29394989, 29339979, 29338080, 32042831, 31853058, 29884841, 32875559, 33293522, 35665744, 35736817, 33609447, 12228710)
Department of Medical Genetics, Oslo University Hospital	RCV000077430	SCV000605687	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130671	SCV002053651	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-09-13	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 2726 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impact BRCA2 function in homology-mediated repair assay (PMID: 23108138, 29394989, 33609447, 35736817) and stable expression in and rescue of Brca2-deficient mouse embryonic stem cells (PMID: 33293522). This variant has been reported in at least two individuals affected with breast cancer (PMID: 25452441, 33471991; Leiden Open Variation Database DB-ID BRCA2_000294) and suspected hereditary breast and ovarian cancer families (PMID: 27495310, 29339979) and an individual affected with prostate cancer (PMID: 33293522). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000212271	SCV004010227	likely pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	BRCA2: PM2, PS4:Moderate, PP1, PS3:Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045442	SCV004039112	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8177A>G (p.Tyr2726Cys) results in a non-conservative amino acid change located in the BRCA2, OB1 (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250998 control chromosomes. c.8177A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Examples: Couch_2015, Jarhelle_2016, Nurmi_2022, Cunningham_2014) and a patient with Pancreatic adenocarcinoma (O'Reily_2018). One publication reports experimental evidence demonstrating it's inability to rescue cell lethality in a null cell line (Biswas_2020) and several report damaging impact on homology-mediated repair assay (Examples: Guidugli_2018, Richardson_2021). The HDR assay qualifies as a standardized gold-standard assay on the basis of the updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) Working Group (Brnich_2019). The following publications have been ascertained in the context of this evaluation (PMID: 20215541, 19043619, 33293522, 25452441, 24504028, 23108138, 24323938, 29394989, 27495310, 36551643, 29338080, 33609447). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classify as VUS (n=1), likely pathogenic (n=5) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003473416	SCV004212817	likely pathogenic	Familial cancer of breast	2022-04-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212271	SCV004220591	likely pathogenic	not provided	2023-02-13	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0000087 (1/114620 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with prostate cancer (PMID: 32875559 (2020)), and hereditary breast and/or ovarian cancer (PMID: 25452441 (2015), 27495310 (2016), 28888541 (2017), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). Functional studies have demonstrated this variant to be non-functional due to deficient homology-directed repair (HDR) (PMIDs: 23108138 (2013), 29394989 (2018), 35736817 (2022)). 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. Based on the available information, this variant is classified as likely pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212271	SCV004565188	pathogenic	not provided	2023-01-04	criteria provided, single submitter	clinical testing	The BRCA2 c.8177A>G; p.Tyr2726Cys variant (rs80359064) is reported in the literature in individuals with BRCA2-associated cancers (Couch 2015, Heramb 2018, Lilyquist 2017, Wokolorczyk 2020), and reported to have impaired homology-directed repair activity (Guidugli 2018, Hu 2022). This variant is also reported by multiple laboratories in ClinVar (Variation ID: 52520). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.928). Based on available information, this variant is considered to be pathogenic. References: Couch FJ et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015 Feb 1;33(4):304-11. PMID: 25452441. Guidugli L et al. Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches. Am J Hum Genet. 2018 Feb 1;102(2):233-248. PMID: 29394989. Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Jan 10;16:3. PMID: 29339979. Hu C et al. Classification of BRCA2 Variants of Uncertain Significance (VUS) Using an ACMG/AMP Model Incorporating a Homology-Directed Repair (HDR) Functional Assay. Clin Cancer Res. 2022 Sep 1;28(17):3742-3751. PMID: 35736817. Lilyquist J et al. Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. Gynecol Oncol. 2017 Nov;147(2):375-380. PMID: 28888541. Wokolorczyk D et al. Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland. Int J Cancer. 2020 Nov 15;147(10):2793-2800. PMID: 32875559.
All of Us Research Program, National Institutes of Health	RCV000077430	SCV004845618	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 2726 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impact BRCA2 function in homology-mediated repair assay (PMID: 23108138, 29394989, 33609447, 35736817) and stable expression in and rescue of Brca2-deficient mouse embryonic stem cells (PMID: 33293522). This variant has been reported in at least two individuals affected with breast cancer (PMID: 25452441, 33471991; Leiden Open Variation Database DB-ID BRCA2_000294) and suspected hereditary breast and ovarian cancer families (PMID: 27495310, 29339979) and an individual affected with prostate cancer (PMID: 33293522). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077430	SCV000109228	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-11-30	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077430	SCV000147292	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Department of Medical Genetics, University Hospital of North Norway	RCV000077430	SCV000301453	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-05-01	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077430	SCV004243806	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing