Submissions for variant NM_000059.4(BRCA2):c.3914_3915del (p.Phe1305fs)

dbSNP: rs397507698

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781037	SCV000918808	likely pathogenic	Hereditary breast ovarian cancer syndrome	2019-12-06	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3914_3915delTT (p.Phe1305CysfsX2) 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 208654 control chromosomes (gnomAD). To our knowledge, no occurrence of c.3914_3915delTT in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV001021425	SCV001183041	pathogenic	Hereditary cancer-predisposing syndrome	2018-07-09	criteria provided, single submitter	clinical testing	The c.3914_3915delTT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 3914 to 3915, causing a translational frameshift with a predicted alternate stop codon (p.F1305Cfs*2). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000781037	SCV001592523	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe1305Cysfs*2) 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 variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 633101). For these reasons, this variant has been classified as Pathogenic.
Sema4, Sema4	RCV001021425	SCV002533834	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV004001528	SCV004838377	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-13	criteria provided, single submitter	clinical testing	This variant deletes 2 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. To our knowledge, this variant has not been reported in individuals affected with BRCA2-related disorders in the literature. 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.
Clinical and Molecular Pathology, Medical Center Transhelix	RCV004001528	SCV005688787	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing	Variant c.3914_3915 causes the loss of two nucleotides in exon 11 of BRCA2 gene. This sequence alteration creates a frameshift (Phe1305CysfsTer2) and a consequent premature stop codon, leading to a non-functional polypeptide chain. Loss-of-function variants in BRCA genes are a known cancer-causing mechanism (PMID: 27452521) (PVS1). This variant is absent from population databases (PM2) (https://gnomad.broadinstitute.org/ version 4.1.0.). Our laboratory has detected BRCA2:c.3914_3915delTT variant in an individual affected with Hereditary Breast and Ovarian Cancer (PP4). This variant [IDs: 633101] has been identified as pathogenic three times (PP5). In conclusion, the ACMG/AMP criteria (MET criteria: PVS1, PM2, PP4, PP5) can be used to interpret the BRCA2:c.3914_3915 variant as pathogenic.
Clinical and Molecular Pathology, Medical Center Transhelix	RCV005231324	SCV005873576	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-11-25	criteria provided, single submitter	clinical testing	Variant c.3914_3915 causes the loss of two nucleotides in exon 11 of BRCA2 gene. This sequence alteration creates a frameshift (Phe1305CysfsTer2) and a consequent premature stop codon, leading to a non-functional polypeptide chain. Loss-of-function variants in BRCA genes are a known cancer-causing mechanism (PMID: 27452521) (PVS1). This variant is absent from population databases (PM2) (https://gnomad.broadinstitute.org/ version 4.1.0.). Our laboratory has detected BRCA2:c.3914_3915delTT variant in an individual affected with Hereditary Breast and Ovarian Cancer (PP4). This variant [IDs: 633101] has been identified as pathogenic three times (PP5). In conclusion, the ACMG/AMP criteria (MET criteria: PVS1, PM2, PP4, PP5) can be used to interpret the BRCA2:c.3914_3915 variant as pathogenic.