Submissions for variant NM_000059.4(BRCA2):c.4133_4136del (p.Thr1378fs)

dbSNP: rs80359430

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113277	SCV000300712	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	RCV000044356	SCV000072369	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr1378Argfs*9) 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 (PMID: 22460208). ClinVar contains an entry for this variant (Variation ID: 51602). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000220994	SCV000276130	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-25	criteria provided, single submitter	clinical testing	The c.4133_4136delCTCA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 4133 to 4136, causing a translational frameshift with a predicted alternate stop codon (p.T1378Rfs*9). 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	RCV000113277	SCV000326977	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000220994	SCV001344939	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-07	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides 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 observed in at least one individual affected with breast cancer (PMID: 18824701, 19340607), two individuals affected with ovarian cancer (PMID: 32438681) and a suspected hereditary breast and ovarian cancer family (PMID: 22460208). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044356	SCV001442673	pathogenic	Hereditary breast ovarian cancer syndrome	2020-10-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4133_4136delCTCA (p.Thr1378ArgfsX9) 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 246502 control chromosomes. c.4133_4136delCTCA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Sinclair_2002, Spearman_2008, Beristain_2010, Rebbeck_2018). 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. Five ClinVar submitters (including two expert panels) have cited the variant as pathogenic (evaluation after 2014). Based on the evidence outlined above, the variant was classified as pathogenic.
Sema4, Sema4	RCV000220994	SCV002533850	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-10	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV003137578	SCV003824362	likely pathogenic	not provided	2022-10-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473336	SCV004210407	pathogenic	Familial cancer of breast	2023-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV003137578	SCV005334403	pathogenic	not provided	2024-03-25	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 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 4361del4; This variant is associated with the following publications: (PMID: 31853058, 18824701, 32438681, 20104584, 29446198, 19340607, 22460208, 36292577, 36324133, 12097257)
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113277	SCV000146379	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044356	SCV000587701	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV000113277	SCV005061324	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-05-24	no assertion criteria provided	case-control