ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.406dupA (p.Arg136Lysfs) (rs80357709)

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Total submissions: 7
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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) RCV000112503 SCV000299453 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000048433 SCV000076446 pathogenic Hereditary breast and ovarian cancer syndrome 2016-01-01 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 6 of the BRCA1 mRNA (c.406dupA), causing a frameshift at codon 136. This creates a premature translational stop signal (p.Arg136Lysfs*6) and is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. This particular truncation has been reported in breast cancer affected individuals from a family with a strong history of breast and ovarian cancers (PMID: 10880552). This variant is also known as 525insA in the literature. ClinVar contains an entry for this variant (Variation ID: 55095). For these reasons, this variant has been classified as Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112503 SCV000325835 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000484275 SCV000568434 pathogenic not provided 2016-01-08 criteria provided, single submitter clinical testing This duplication of one nucleotide in BRCA1 is denoted c.406dupA at the cDNA level and p.Arg136LysfsX6 (R136KfsX6) at the protein level. This variant is also known as BRCA1 525insA using alternate nomenclature. The normal sequence, with the base that is duplicated in braces, is CAAA[A]GACT. The duplication causes a frameshift, which changes an Arginine to a Lysine at codon 136, and creates a premature stop codon at position 6 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. BRCA1 c.406dupA has been observed in association with ovarian cancer (Werness 2000). We consider this variant to be pathogenic.
Ambry Genetics RCV000510018 SCV000608214 pathogenic Hereditary cancer-predisposing syndrome 2017-05-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484275 SCV000887683 pathogenic not provided 2017-08-31 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112503 SCV000145325 pathogenic Breast-ovarian cancer, familial 1 1998-11-23 no assertion criteria provided clinical testing

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