Submissions for variant NM_007299.4(BRCA1):c.425C>A (p.Pro142His) (rs55971303)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112613	SCV000244358	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 = 0.00000103
Invitae	RCV000203643	SCV000076518	benign	Hereditary breast and ovarian cancer syndrome	2017-12-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000259147	SCV000209908	benign	not specified	2017-07-11	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	RCV000162718	SCV000213180	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000034749	SCV000231725	uncertain significance	not provided	2014-09-04	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories,University of Michigan	RCV000112613	SCV000267680	likely benign	Breast-ovarian cancer, familial 1	2016-04-21	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000259147	SCV000591265	likely benign	not specified	2016-09-23	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000034749	SCV000699126	likely benign	not provided	2016-03-16	criteria provided, single submitter	clinical testing	Variant summary: The c.425C>A variant affects a non-conserved nucleotide, resulting in amino acid change from Pro to His. 3/4 in-silico tools predict this variant to be damaging. This variant was found in 7/122892 control chromosomes from the large and broad populations from ExAC at a frequency of 0.000057, which is lower that the maximal expected frequency of a pathogenic allele (0.0010005) in this gene. The variant has been reported in multiple patients with breast and/or ovarian cancer without strong evidence for causality. The variant is found to co-occur with other deleterious variants in BRCA1/2 including its presence in trans with a known pathogenic variant BRCA1 187delAG aka c.68_69delAG (Judkins_2005/BIC) and BRCA2 c.5576_5579delTTAA (UMD), a very strong evidence that the variant should be benign. Although drug sensitivity, E2 interaction, and homology-directed recombination (HDR) assays were normal, single-strand annealing (SSA) was impaired (Bouwman_2013,Towler_2013, Wei_2008, Morris_2006). Multiple clinical laboratories as well as reputable databases have classified this variant as benign/likely benign. Multifactorial probability based model also shows the variant to be benign (Lindor_2012, Easton_2007). Taken together, this variant has been classified as Likely Benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034749	SCV000883460	likely benign	not provided	2017-11-06	criteria provided, single submitter	clinical testing	The BRCA1 c.425C>A; p.Pro142His variant is published in the medical literature as having a low probability of pathogenicity (Chenevix-Trench 2006, Lindor 2012). The variant is listed in the ClinVar database (Variation ID: 41823) as benign or likely benign by the majority of submitters. The variant is listed in the dbSNP variant database (rs55971303) and in the Genome Aggregation Database in 25/276378 alleles. The proline at this position is moderately conserved across species, with at least one mammal with a serine at this position. Additionally, functional studies show this variant can function as the wild type protein (Bouwman 2013). Considering available information, this variant is classified as likely benign. References: Bouwman P et al. A high-throughput functional complementation assay for classification of BRCA1 missense variants. Cancer Discov. 2013 Oct;3(10):1142-55. Chenevix-Trench G et al. Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance. Cancer Res. 2006 Feb 15;66(4):2019-27. Lindor NM et al. A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). Hum Mutat. 2012 Jan;33(1):8-21.
Color	RCV000162718	SCV000910791	benign	Hereditary cancer-predisposing syndrome	2016-05-02	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health	RCV000034749	SCV000043188	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112613	SCV000145455	uncertain significance	Breast-ovarian cancer, familial 1	2002-05-29	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000112613	SCV000297609	benign	Breast-ovarian cancer, familial 1	2006-06-23	no assertion criteria provided	clinical testing