Submissions for variant NM_000059.4(BRCA2):c.1642C>T (p.Gln548Ter)

dbSNP: rs398122729

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077662	SCV000300450	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.
Ambry Genetics	RCV000130404	SCV000185264	pathogenic	Hereditary cancer-predisposing syndrome	2024-04-18	criteria provided, single submitter	clinical testing	The p.Q548* pathogenic mutation (also known as c.1642C>T), located in coding exon 9 of the BRCA2 gene, results from a C to T substitution at nucleotide position 1642. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077662	SCV000326581	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000077662	SCV000605669	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000823651	SCV000964518	pathogenic	Hereditary breast ovarian cancer syndrome	2024-07-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln548*) 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 personal or family history of breast and/or ovarian cancer (PMID: 28008555, 29084914, 29339979). ClinVar contains an entry for this variant (Variation ID: 91754). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800382	SCV002047304	pathogenic	not provided	2021-05-18	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been described in individuals with breast cancer and ovarian cancer in the published literature (PMID: 29084914 (2018), 28008555 (2017)). This variant has not been reported in large, multi-ethnic general populations. Based on the available information, this variant is classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000077662	SCV004826983	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-19	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 10 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: 28008555, 29084914, 29446198). 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.
Sharing Clinical Reports Project (SCRP)	RCV000077662	SCV000109465	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2010-09-08	no assertion criteria provided	clinical testing