ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1389_1390delinsG (p.Thr464fs) (rs273897659)

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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) RCV000030990 SCV000299592 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000213424 SCV000278779 pathogenic Hereditary cancer-predisposing syndrome 2019-01-09 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000462415 SCV000549270 pathogenic Hereditary breast and ovarian cancer syndrome 2018-08-07 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides and inserts 1 nucleotide in exon 10 of the BRCA1 mRNA (c.1389_1390delinsG), causing a frameshift at codon 464. This creates a premature translational stop signal (p.Thr464Profs*11) and is expected to result in an absent or disrupted protein product. While this variant has not been reported in the literature, two different variants, c.1390delA (also known as c.1387delA and c.1506delA) and c.1386delG (also known as c.1505delG), giving rise to the same protein effect observed here (p.Thr464Profs*11) have been reported in individuals affected with breast/and or ovarian cancer (PMID: 10866029, 27836010, 8807330). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000487351 SCV000566059 pathogenic not provided 2015-03-20 criteria provided, single submitter clinical testing This combined deletion and insertion is denoted c.1389_1390delAAinsG at the cDNA level and p.Thr464ProfsX11 (T464PfsX11) at the protein level. Using alternate nomenclature, this variant would be defined as c.1508delAAinsG. The normal sequence, with the bases that are deleted and inserted in brackets, is GGAA[delAA][insG]CCTA. The variant causes a frameshift, which changes a Threonine to a Proline at codon 464, and creates a premature stop codon at position 11 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider BRCA1 c.1389_1390delAAinsG to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000462415 SCV000918677 pathogenic Hereditary breast and ovarian cancer syndrome 2018-04-02 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1389_1390delinsG (p.Thr464ProfsX11) 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 (eg. c.1480C>T (p.Gln494X), c.1492delC (p.Leu498fsX5), and c.1508delA (p.Lys503fsX29)). The variant was absent in 245916 control chromosomes (gnomAD). The variant, c.1389_1390delinsG, has not been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. However, other variants such as c.1390delA (legacy names: c.1387delA, 1506delA) and c.1386delA (legacy name: 1505delG) that cause the same frameshift mutation have been reported in affected HBOC patients (Couch_1996, Peyrat_1998, Rebbeck_2016). Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000030990 SCV000053582 pathogenic Breast-ovarian cancer, familial 1 2010-12-23 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000030990 SCV000144078 pathogenic Breast-ovarian cancer, familial 1 2001-10-29 no assertion criteria provided clinical testing

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