Submissions for variant NM_000059.4(BRCA2):c.1888dup (p.Thr630fs)

dbSNP: rs80359314

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)	RCV000077671	SCV000300475	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	RCV000509652	SCV000608069	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-11	criteria provided, single submitter	clinical testing	The c.1888dupA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a duplication of A at nucleotide position 1888, causing a translational frameshift with a predicted alternate stop codon (p.T630Nfs*6). This alteration has been identified in individuals diagnosed with ovarian cancer, breast cancer and melanoma (Walsh T et al. Proc. Natl. Acad. Sci. U.S.A., 2011 Nov;108:18032-7; Kwong A et al. J Mol Diagn, 2016 07;18:580-94; Yang XR et al. Breast Cancer Res Treat, 2017 Oct;165:687-697; Amaral T et al. Cancers (Basel), 2020 Apr;12:). This alteration has also been identified in an individual with a family history of pancreatic cancer (Abe T et al. J Clin Oncol, 2019 05;37:1070-1080). 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	RCV000779917	SCV000916843	pathogenic	Hereditary breast ovarian cancer syndrome	2019-11-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1888dupA (p.Thr630AsnfsX6) 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 240976 control chromosomes (gnomAD). c.1888dupA has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer and bile duct carcinoma (Walsh_2011, Kwong_2016, Yang_2017, Pennington_2013, Terashima_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) including an expert panel, ENIGMA, cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001091961	SCV001248267	pathogenic	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262274	SCV001440085	pathogenic	Familial cancer of breast	2023-07-02	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4,PM2_SUP
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001091961	SCV001470407	pathogenic	not provided	2019-11-07	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000779917	SCV001592374	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr630Asnfs*6) 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 breast and/or ovarian cancer and breast cancer and ovarian cancer (PMID: 22006311, 27157322, 28664506). This variant is also known as c.2116insA. ClinVar contains an entry for this variant (Variation ID: 51220). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001091961	SCV001820382	pathogenic	not provided	2019-08-30	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 in large population cohorts (Lek et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 31666926, 29337092, 27157322, 28664506, 22006311)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492347	SCV004240296	likely pathogenic	Breast and/or ovarian cancer	2022-09-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000509652	SCV004361242	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-09	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 10 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 2116insA and c.1887_1888insA in the literature. 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 detected in at least three individuals affected with breast and/or ovarian cancer (PMID: 24240112, 27157322, 28664506) and one individual each affected with pancreatic cancer and biliary tract cancer (PMID: 30883245, 31666926). 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)	RCV000077671	SCV000109474	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-29	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077671	SCV000145971	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing