Submissions for variant NM_032043.3(BRIP1):c.1760A>T (p.His587Leu)

dbSNP: rs876660646

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216569	SCV000278250	likely benign	Hereditary cancer-predisposing syndrome	2024-03-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000219246	SCV000279642	uncertain significance	not provided	2017-11-13	criteria provided, single submitter	clinical testing	This variant is denoted BRIP1 c.1760A>T at the cDNA level, p.His587Leu (H587L) at the protein level, and results in the change of a Histidine to a Leucine (CAT>CTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 His587Leu was not observed in large population cohorts (Lek 2016). Since Histidine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether BRIP1 His587Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460900	SCV000547349	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 587 of the BRIP1 protein (p.His587Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 31822495). ClinVar contains an entry for this variant (Variation ID: 233799). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRIP1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRIP1 function (PMID: 31822495). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl	RCV000662901	SCV000785822	uncertain significance	Fanconi anemia complementation group J; Ovarian neoplasm	2017-12-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000216569	SCV001347349	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-07	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with leucine at codon 587 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant shows wild-type activity in the rescue of cytotoxicity caused by DNA damaging agents (PMID: 31822495). This variant has been reported in individuals affected with breast cancer in the literature (PMID: 31822495). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194199	SCV001363546	uncertain significance	not specified	2019-04-18	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.1760A>T (p.His587Leu) results in a non-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 was absent in 251434 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1760A>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV003316230	SCV004019301	uncertain significance	Familial cancer of breast	2023-02-27	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV003316230	SCV004217070	uncertain significance	Familial cancer of breast	2024-03-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000460900	SCV005654121	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-05-22	criteria provided, single submitter	clinical testing