Submissions for variant NM_000059.4(BRCA2):c.2409T>G (p.Tyr803Ter)

dbSNP: rs80358504

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031365	SCV000300516	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000043984	SCV000071997	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr803*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 21324516, 22711857). ClinVar contains an entry for this variant (Variation ID: 37784). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000212221	SCV000210287	pathogenic	not provided	2021-01-05	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with a personal and/or family history of BRCA2-related cancers (Zhang 2011, Alsop 2012, Rebbeck 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 21324516, 25525159, 22711857, 21702907, 29446198, 32885271)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031365	SCV000326700	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000043984	SCV000605811	pathogenic	Hereditary breast ovarian cancer syndrome	2019-04-24	criteria provided, single submitter	clinical testing	The p.Tyr803X variant in BRCA2 has been reported in at least 2 individuals with BRCA2-associated cancers (Breast Cancer Information Core (BIC) database, Zhang 2011) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 803, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300516.2). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting.
Ambry Genetics	RCV000573627	SCV000661153	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-04	criteria provided, single submitter	clinical testing	The p.Y803* pathogenic mutation (also known as c.2409T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 2409. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This alteration was identified in multiple cohorts of individuals diagnosed with ovarian cancer (Zhang S et al. Gynecol. Oncol. 2011 May;121(2):353-7; Alsop K et al. J. Clin. Oncol. 2012 Jul;30(21):2654-63). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620) and in 1/50726 patients from an unselected population cohort from a single health system who underwent exome sequencing (Manickam K et al. JAMA Netw Open, 2018 09;1:e182140). Of note, this alteration is also designated as 2637T>G in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000043984	SCV000694604	pathogenic	Hereditary breast ovarian cancer syndrome	2022-10-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2409T>G (p.Tyr803X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 248736 control chromosomes. c.2409T>G has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Hondow_2011, Zhang_2011, Rebbeck_2018, Hollis_2020). These data indicate that the variant is very likely to be associated with disease. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000212221	SCV000805673	pathogenic	not provided	2018-01-04	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769686	SCV000901099	pathogenic	Breast and/or ovarian cancer	2017-04-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000573627	SCV000905006	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-07	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 3 individuals affected with ovarian cancer, 1 individual affected with breast cancer (PMID: 21324516, 22711857, 33808557, Color internal data), and has been identified in 4 families among the CIMBA participants (PMID: 29446198). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 1/53461 controls (OR=0.884. 95%CI 0.055 to 14.136; p-value=1) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_00436). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Sema4, Sema4	RCV000573627	SCV002535497	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-05	criteria provided, single submitter	curation
Baylor Genetics	RCV003473164	SCV004210551	pathogenic	Familial cancer of breast	2022-06-24	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031365	SCV000053970	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-09-21	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031365	SCV000146038	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	1999-12-30	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000043984	SCV000587631	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000031365	SCV000591806	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The BRCA2 p.Tyr803X variant was identified in the literature in an individual with invasive ovarian cancer (Zhang 2011). The variant was also identified in dbSNP (ID: rs80358504) “With pathogenic allele”, HGMD, and the BIC database (1X with clinical importance). The p.Tyr803X variant leads to a premature stop codon at position 803, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.