Submissions for variant NM_000059.4(BRCA2):c.4325C>A (p.Ser1442Ter)

dbSNP: rs80358670

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)	RCV000113295	SCV000300737	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044395	SCV000072408	pathogenic	Hereditary breast ovarian cancer syndrome	2024-11-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1442*) 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 present in population databases (rs80358670, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with BRCA2-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 51633). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000505839	SCV000296602	pathogenic	not provided	2021-01-22	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in an individual with breast and/or ovarian cancer in the published literature (PMID: 32438681 (2020)). It has also been identified in a large cohort of BRCA1 and BRC2 mutation carriers (PMID 29446198 (2018)). Therefore, the variant is classified as pathogenic and this individual is at increased risk of developing BRCA2 related cancers.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113295	SCV000327015	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000510062	SCV000607776	pathogenic	Hereditary cancer-predisposing syndrome	2024-08-01	criteria provided, single submitter	clinical testing	The p.S1442* pathogenic mutation (also known as c.4325C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 4325. This changes the amino acid from a serine to a stop codon within coding exon 10. 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.
GeneDx	RCV000505839	SCV000617998	pathogenic	not provided	2024-04-19	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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4553C>A; This variant is associated with the following publications: (PMID: 29922827, 28186126, 28152038, 29446198, 30720243, 30787465, 34308104, 31853058, 32377563, 32438681, 31869745)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002014	SCV001159830	pathogenic	not specified	2018-07-22	criteria provided, single submitter	clinical testing	The BRCA2 c.4325C>A; p.Ser1442Ter variant (rs80358670), is reported in the literature in a validation study of pathogenic hereditary cancer variants (LaDuca 2017). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 51633), and is only observed on one allele in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: LaDuca H et al. Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels. PLoS One. 2017 Feb 2;12(2):e0170843.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044395	SCV001364001	pathogenic	Hereditary breast ovarian cancer syndrome	2019-03-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4325C>A (p.Ser1442X) 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 (c.4415_4418delAGAA, p.Lys1472fsX6; c.4551_4554delAGAA, p.Lys1517fsX25; c.5682C>G, p.Tyr1894X). The variant allele was found at a frequency of 4.2e-06 in 237016 control chromosomes (gnomAD). This variant has been reported in the literature in individuals presumably affected with Hereditary Breast and Ovarian Cancer (Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six CliNVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003473339	SCV004210552	pathogenic	Familial cancer of breast	2023-12-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004803177	SCV005424428	pathogenic	BRCA2-related cancer predisposition	2024-03-24	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 individuals with a personal or family history of breast and/or ovarian cancer (PMID: 29446198, 32438681). This variant has been identified in 1/241106 chromosomes 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113295	SCV000146409	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044395	SCV000587709	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research