Submissions for variant NM_032043.3(BRIP1):c.617C>T (p.Ser206Leu)

gnomAD frequency: 0.00002  dbSNP: rs565458815

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168335	SCV000219024	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 206 of the BRIP1 protein (p.Ser206Leu). This variant is present in population databases (rs565458815, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and colorectal cancer (PMID: 31206626, 33309985). ClinVar contains an entry for this variant (Variation ID: 188324). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRIP1 protein function. 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.
Ambry Genetics	RCV000222015	SCV000275787	likely benign	Hereditary cancer-predisposing syndrome	2018-05-07	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506651	SCV000600926	uncertain significance	not specified	2016-12-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000222015	SCV000689404	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 206 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in breast and ovarian cancer case control studies in 0/60466 breast cancer cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRIP1_000670) and in 0/3236 ovarian cancer cases and 1/3431 unaffected individuals (PMID: 26315354). This variant also has been reported in a colorectal and prostate cancer case-control studies in 1/12503 colorectal cancer cases and 0/23705 unaffected individuals (PMID: 33309985) and in 1/7636 prostate cancer cases and 0/12366 unaffected individuals (PMID: 31214711). This variant has been identified in 5/282696 chromosomes 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.
Counsyl	RCV000662572	SCV000785181	uncertain significance	Fanconi anemia complementation group J; Ovarian neoplasm	2017-05-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000506651	SCV001519431	uncertain significance	not specified	2022-02-07	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.617C>T (p.Ser206Leu) results in a non-conservative amino acid change located in the Helicase superfamily 1/2, ATP-binding domain (IPR014001) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251312 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.617C>T has been reported in the literature in an individual affected with Breast Cancer (example, Weitzel_2019), and another individual affected with colorectal cancer (example, Fujita_2020), but was also found in controls (example, Ramus_2015, Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. At-least two co-occurrences with other pathogenic variant(s) have been observed at our laboratory (BARD1 c.1872delT , p.Leu625SerfsX7 ; BRCA1 c.(4986+1_4987-1)_(5074+1_5075-1)del [exon 16 del]), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=5, Likely Benign, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
GeneDx	RCV001546767	SCV001766347	uncertain significance	not provided	2023-09-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with personal or family history of breast/ovarian cancer and also in unaffected controls (Ramus et al., 2015; Weitzel et al., 2019); This variant is associated with the following publications: (PMID: 27545006, 31839986, 31206626, 33309985, 26315354)
Sema4, Sema4	RCV000222015	SCV002533728	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-19	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003316070	SCV004019391	uncertain significance	Familial cancer of breast	2023-02-28	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	RCV003316070	SCV004214698	uncertain significance	Familial cancer of breast	2023-11-16	criteria provided, single submitter	clinical testing