ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.628C>T (p.Pro210Ser) (rs150313156)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130394 SCV000185253 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000662423 SCV000784874 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-01-20 criteria provided, single submitter clinical testing
GeneDx RCV000590600 SCV000329150 uncertain significance not provided 2018-01-16 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.628C>T at the cDNA level, p.Pro210Ser (P210S) at the protein level, and results in the change of a Proline to a Serine (CCC>TCC). This variant has been observed in one control subject (1/3431) but not in a cohort of women with a history of epithelial ovarian cancer (0/3236) (Ramus 2015). This variant was also observed in an individual with colon cancer whose tumor was mismatch repair deficient, co-occurring with a truncating MLH1 variant (Pearlman 2017). BRIP1 Pro210Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Pro210Ser is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRIP1 Pro210Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590600 SCV000699733 likely benign not provided 2017-07-14 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.628C>T (p.Pro210Ser) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 6/127176 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.000496 (5/10084). This frequency is about 8 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant is the first nucleotide in exon 7, but 5/5 splice prediction tools predict no significant impact on normal splicing. This variant has been reported in one CRC patient with co-occurrence of a pathogenic variant in MLH1 c.1381A>T/p.K461X. In addition, one internal sample had co-occurrence with another two pathogenic variants PMS2 c.2186_2187delTC/p.L729fsX6 and PALB2 c.3323delA/p.Y1108fsX16, further supporting the benign nature of this variant. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, all without evidence for independent evaluation. Taken together, this variant is classified as likely benign until more evidence becomes available.
Invitae RCV000200420 SCV000255178 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 210 of the BRIP1 protein (p.Pro210Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs150313156, ExAC 0.05%). This variant has been reported in an individual affected with colorectal cancer (PMID: 27978560). However, in that individual a pathogenic allele was also identified in MLH1, and the clinical significance of this c.628C>T variant remains uncertain. ClinVar contains an entry for this variant (Variation ID: 141761). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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