ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.590C>T (p.Ser197Phe) (rs533184563)

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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 RCV000131156 SCV000186098 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000131156 SCV000684290 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-08 criteria provided, single submitter clinical testing
GeneDx RCV000235300 SCV000293224 uncertain significance not provided 2017-10-23 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.590C>T at the cDNA level, p.Ser197Phe (S197F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCT>TTT). In a large case-control study, this variant was observed in 1/13,213 breast cancer patients, apparently in the homozygous state, and in 1/5242 controls in one cohort and in 1/1313 breast cancer cases and absent in 1123 controls in a second cohort (Easton 2016). BRIP1 Ser197Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Serine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Ser197Phe occurs at a position that is conserved in mammals and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRIP1 Ser197Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000198544 SCV000255177 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-23 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 197 of the BRIP1 protein (p.Ser197Phe). The serine residue is weakly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast cancer (PMID: 26921362) and prostate cancer (PMID: 29368341). ClinVar contains an entry for this variant (Variation ID: 142178). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825289 SCV000966584 uncertain significance not specified 2019-01-03 criteria provided, single submitter clinical testing The p.Ser197Phe variant in BRIP1 has been reported in 2 European individuals wit h breast cancer, once in the homozygous state and once in the heterozygous state , as well as one heterozygous individual with prostate cancer (Easton 2016, Velh o 2018). This variant has also been identified in 0.008% (2/24964) of African ch romosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. Furthermore, although the BRIP1 gene has been reported i n association with multiple cancer types, a ClinGen Expert Panel has only defini tively associated the gene to ovarian cancer and refuted its association with br east cancer. There also appears to be limited evidence for an association with p rostate cancer and no good evidence for an association with colon cancer. In sum mary, the clinical significance of the p.Ser197Phe variant is uncertain. ACMG/AM P Criteria applied: PM2_Supporting.

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