ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4127_4130del (p.Gly1376fs) (rs397507323)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031461 SCV000300710 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000204198 SCV000259300 pathogenic Hereditary breast and ovarian cancer syndrome 2020-07-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly1376Alafs*11) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 25428789). This variant is also known as 4355del4 in the literature. ClinVar contains an entry for this variant (Variation ID: 37880). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000255023 SCV000321458 pathogenic not provided 2018-09-07 criteria provided, single submitter clinical testing This deletion of 4 nucleotides in BRCA2 is denoted c.4127_4130delGAAA at the cDNA level and p.Gly1376AlafsX11 (G1376AfsX11) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GAGG[delGAAA]CACT. The deletion causes a frameshift, which changes a Glycine to an Alanine at codon 1376, and creates a premature stop codon at position 11 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.4127_4130delGAAA, previously reported as BRCA2 4355del4 using alternate nomenclature, has been observed in at least one individual with breast cancer (Churpek 2015). We consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031461 SCV000326975 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031461 SCV000488468 likely pathogenic Breast-ovarian cancer, familial 2 2016-04-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000255023 SCV000600575 pathogenic not provided 2016-12-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000567586 SCV000665977 pathogenic Hereditary cancer-predisposing syndrome 2019-03-25 criteria provided, single submitter clinical testing The c.4127_4130delGAAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 4127 to 4130, causing a translational frameshift with a predicted alternate stop codon (p.G1376Afs*11). This mutation was reported in an African American woman diagnosed with breast cancer (Churpek JE et al. Breast Cancer Res. Treat. 2015 Jan;149(1):31-9). 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.
Sharing Clinical Reports Project (SCRP) RCV000031461 SCV000054066 pathogenic Breast-ovarian cancer, familial 2 2012-04-25 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000204198 SCV000587700 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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