Submissions for variant NM_007294.4(BRCA1):c.1670_1673del (p.Thr557fs)

dbSNP: rs1555591390

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000661247	SCV000783510	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-12-15	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001280612	SCV001467831	likely pathogenic	Hereditary breast ovarian cancer syndrome	2020-12-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1670_1673delCAAA (p.Thr557LysfsX14) 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 250426 control chromosomes. c.1670_1673delCAAA has been reported in the literature in at-least one individual with anorectal melanoma (Yang_2017) and in one family affected with Hereditary Breast And Ovarian Cancer Syndrome (Laitman_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One expert panel (ENIGMA) has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.