Submissions for variant NM_032043.3(BRIP1):c.10A>G (p.Met4Val)

gnomAD frequency: 0.00001  dbSNP: rs45512093

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216902	SCV000276378	likely benign	Hereditary cancer-predisposing syndrome	2018-10-12	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467101	SCV000547247	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 4 of the BRIP1 protein (p.Met4Val). This variant is present in population databases (rs45512093, gnomAD 0.003%). This missense change has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer or clinical features of Lynch syndrome (PMID: 25980754, 26921362, 31159747). ClinVar contains an entry for this variant (Variation ID: 232285). 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%. 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.
GeneKor MSA	RCV000216902	SCV000821952	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000216902	SCV000903620	likely benign	Hereditary cancer-predisposing syndrome	2017-02-23	criteria provided, single submitter	clinical testing
GeneDx	RCV003148687	SCV003837182	uncertain significance	not provided	2023-02-28	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 breast cancer or a history of Lynch syndrome-associated cancer and/or colon polyps (Yurgelun et al., 2015; Easton et al., 2016); This variant is associated with the following publications: (PMID: 25980754, 31159747, 26921362, 31742824)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767177	SCV005380611	uncertain significance	not specified	2024-08-12	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.10A>G (p.Met4Val) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251232 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.10A>G has been reported in the literature in individuals with a diagnosis of or predisposition to hereditary cancer (e.g. Tsaousis_2019, Shao_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Complementation Group J. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31742824, 31159747). ClinVar contains an entry for this variant (Variation ID: 232285). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354597	SCV001549247	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRIP1 p.Met4Val variant was identified in 2 of 5146 proband chromosomes (frequency: 0.0004) from individuals or families with breast cancer or lynch syndrome and was not identified in 2246 control chromosomes from healthy individuals (Easton 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs45512093) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by Invitae), MutDB, and in the Zhejiang University database. The variant was identified in control databases in 2 of 277002 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: European in 1 of 126564 chromosomes (freq: 0.00001), and South Asian in 1 of 30780 chromosomes (freq: 0.00003); but was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Met4 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.