Submissions for variant NM_000059.4(BRCA2):c.6487C>T (p.Gln2163Ter)

dbSNP: rs398122559

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000076968	SCV000301057	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.
GeneDx	RCV000483318	SCV000572278	pathogenic	not provided	2016-11-11	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.6487C>T at the cDNA level and p.Gln2163Ter (Q2163X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000579895	SCV000683788	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-19	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. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with early-onset breast cancer (Color data). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483318	SCV001133866	pathogenic	not provided	2019-01-28	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Ambry Genetics	RCV000579895	SCV001187487	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-30	criteria provided, single submitter	clinical testing	The p.Q2163* pathogenic mutation (also known as c.6487C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 6487. This changes the amino acid from a glutamine 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192504	SCV001360688	likely pathogenic	Hereditary breast ovarian cancer syndrome	2019-04-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6487C>T (p.Gln2163X) 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 (e.g. c.6656C>G, p.Ser2219X; c.6952C>T, p.Arg2318X; c.7878G>A, p.Trp2626X). The variant was absent in 228928 control chromosomes (gnomAD). To our knowledge, no occurrence of c.6487C>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV001192504	SCV001375060	pathogenic	Hereditary breast ovarian cancer syndrome	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln2163*) 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 BRCA2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 91451). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000483318	SCV004010223	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2
Baylor Genetics	RCV003460722	SCV004216118	pathogenic	Familial cancer of breast	2023-05-24	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000076968	SCV000108765	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-07-06	no assertion criteria provided	clinical testing