ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1000G>A (p.Ala334Thr) (rs535414791)

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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 RCV000219711 SCV000273637 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-16 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000483340 SCV000566782 uncertain significance not provided 2017-11-02 criteria provided, single submitter clinical testing This variant is denoted BRIP1 c.1000G>A at the cDNA level, p.Ala334Thr (A334T) at the protein level, and results in the change of an Alanine to a Threonine (GCC>ACC). This variant has been reported in at least two individuals with breast cancer (Easton 2016). BRIP1 Ala334Thr was not observed at a significant frequency in large population cohorts (Lek 2016). Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Ala334Thr occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRIP1 Ala334Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000536267 SCV000633525 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 334 of the BRIP1 protein (p.Ala334Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs535414791, ExAC 0.02%). This variant has been reported in the literature in individuals affected with breast cancer (PMID: 26921362). ClinVar contains an entry for this variant (Variation ID: 230188). 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.
Color RCV000219711 SCV000905829 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780059 SCV000917081 uncertain significance not specified 2018-05-25 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.1000G>A (p.Ala334Thr) results in a non-conservative amino acid change located in the Helicase superfamily 1/2, ATP-binding domain, DinG/Rad3-type of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The observed variant frequency within African control individuals in the gnomAD database is approximately 3-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), suggesting that the variant is possibly a benign polymorphism found primarily in populations of African origin. The variant, c.1000G>A, has been reported in the literature in individuals affected with Breast Cancer (Easton_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories cite the variant as "uncertian significance." Based on the evidence outlined above, the variant was classified as VUS - possibly benign.

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