Submissions for variant NM_007299.4(BRCA1):c.427G>A (p.Glu143Lys) (rs80356991)

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031161	SCV000244359	benign	Breast-ovarian cancer, familial 1	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000109
Invitae	RCV000048510	SCV000076523	likely benign	Hereditary breast and ovarian cancer syndrome	2017-12-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000159939	SCV000210075	likely benign	not specified	2017-12-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000162967	SCV000213455	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000159939	SCV000538455	uncertain significance	not specified	2016-06-23	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 3 B/LB, including expert panel
Integrated Genetics/Laboratory Corporation of America	RCV000159939	SCV000699128	likely benign	not specified	2019-01-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.427G>A (p.Glu143Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 276560 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (8e-05 vs 0.001), allowing no conclusion about variant significance. c.427G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. The variant has been functionally evaluated and showed similar to wild-type activity in an HDR assay and intermediate activity in a less specific Single strand annealing (SSA) assay (Towler, 2013, Lu, 2015 and Starita, 2018). In addition, this variant has been reported as "1 - Not pathogenic or of no clinical significance" based on posterior probability calculation being 0.000, which combines prior probabilities of causality derived from an evolutionary sequence conservation model and likelihoods of causality derived from measures of associations between the VUS and cancer (FH, segregation, co-occurrence with deleterious variants, and histopathology data; see references Lindor_2012 and Easton_2007). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (4x likely benign and 1x VUS). Our laboratory has classified this variant as a "VUS-possibly normal" in a series of conservative re-evaluations spanning three years (2015-2018), however, no new evidence supporting pathogenicity have been reported and at-least four other testing laboratories have classified this variant as benign/likely benign since our original classification. Therefore, the overall evidence seems to be shifting from uncertain significance to likely benign consistent with at-least three independent reports (spanning 2013-2018) demonstrating no effect on homology directed repair activity (HDR). Based on the evidence outlined above, until more clinical and prevalence data become available, the variant was classified as likely benign.
Counsyl	RCV000031161	SCV000786473	benign	Breast-ovarian cancer, familial 1	2018-05-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588563	SCV000885069	uncertain significance	not provided	2017-09-14	criteria provided, single submitter	clinical testing	The BRCA1 c.427G>A, p.Glu143Lys variant has been reported in patients with breast and/or ovarian cancer (Easton 2007, Lindor 2012). Multi-factorial analysis (based on co-occurrence, tumor pathology, co-segregation and family history) has indicated that the variant has low probability of causation or pathogenicity (Easton 2007, Lindor 2012). The variant is listed in the ClinVar database (Variation ID: 37580), in the dbSNP variant database (rs80356991), and observed at a frequency of 0.007955 percent (22/276560 alleles) in the Genome Aggregation Database, a general population database. The glutamate at residue 143 is moderately conserved, and computational algorithms (Align GV/GD, Mutation Taster, PolyPhen-2) predict that the variant has no impact on the protein. Due to the limited information regarding this variant, its clinical significance could not be determined with certainty, though the available evidence suggests a low likelihood of causing disease. References: Easton D et al. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet. 2007 81(5):873-83. Lindor N et al. A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). Hum Mutat. 2012 33(1):8-21.
Color	RCV000162967	SCV000902846	likely benign	Hereditary cancer-predisposing syndrome	2015-08-20	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031161	SCV000053761	uncertain significance	Breast-ovarian cancer, familial 1	2010-11-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031161	SCV000145475	uncertain significance	Breast-ovarian cancer, familial 1	2004-02-20	no assertion criteria provided	clinical testing