Submissions for variant NM_000059.4(BRCA2):c.4631dup (p.Asn1544fs)

dbSNP: rs80359460

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)	RCV000031493	SCV000300774	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	RCV000044456	SCV000072469	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn1544Lysfs*4) 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 (rs771851449, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast/ovarian cancer, and an individual undergoing testing for Lynch syndrome (PMID: 17688236, 23683081, 24728189, 25980754). This variant is also known as 4859insA. ClinVar contains an entry for this variant (Variation ID: 37912). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000132322	SCV000187408	pathogenic	Hereditary cancer-predisposing syndrome	2024-07-12	criteria provided, single submitter	clinical testing	The c.4631dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 4631, causing a translational frameshift with a predicted alternate stop codon (p.N1544Kfs*4). This mutation has been identified in multiple European breast and/or ovarian cancer families (Al-Mulla F et al. J. Clin. Pathol. 2009 Apr;62(4):350-6; Ramus SJ et al. Hum Mutat, 2007 Dec;28:1207-15; Blay P et al. BMC Cancer. 2013 May 17;13:243; Song H et al. Hum Mol Genet, 2014 Sep;23:4703-9). This mutation was also detected in a cohort of 29,906 healthy individuals who underwent multigene panel testing (Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239). Of note, this alteration is also designated as 4859insA 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000388617	SCV000296705	pathogenic	not provided	2019-08-23	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in affected individuals with breast and/or ovarian cancer in the published literature (PMIDs: 17688236 (2007), 23683081 (2013) and 25980754 (2015)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031493	SCV000327062	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000388617	SCV000329608	pathogenic	not provided	2022-12-22	criteria provided, single submitter	clinical testing	Frameshift 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 a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Ramus et al., 2007; Blay et al., 2013; Song et al., 2014); This variant is associated with the following publications: (PMID: 23683081, 26315209, 29922827, 28888541, 17688236, 25980754, 24728189, 30720243, 32719484, 30787465, Celebi_2022_Case Report, Stoganova_2022_Case Report)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769695	SCV000901110	pathogenic	Breast and/or ovarian cancer	2017-04-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132322	SCV000911166	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 5 individuals affected with breast or ovarian cancer (PMID: 17688236, 22711857, 23683081, 24728189, 28525389), 1 individual suspected to be affected with Lynch Syndrome and (PMID: 25980754), and has been identified in 9 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 2/276320 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044456	SCV000916854	pathogenic	Hereditary breast ovarian cancer syndrome	2018-02-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4631dupA (p.Asn1544LysfsX4) 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. The variant was absent in 245418 control chromosomes (gnomAD). The c.4631dupA variant has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) classify the variant as "pathogenic," in addition, multiple reliable databases also classify the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003460511	SCV004213583	pathogenic	Familial cancer of breast	2024-03-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031493	SCV004845711	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-26	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 5 individuals affected with breast or ovarian cancer (PMID: 17688236, 22711857, 23683081, 24728189, 28525389), 1 individual suspected to be affected with Lynch Syndrome and (PMID: 25980754), and has been identified in 9 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 2/276320 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.
Sharing Clinical Reports Project (SCRP)	RCV000031493	SCV000054098	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2007-08-15	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031493	SCV000146458	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044456	SCV000587718	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
BRCAlab, Lund University	RCV000031493	SCV002588878	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV000031493	SCV005061325	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-05-24	no assertion criteria provided	case-control