ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1109A>G (p.Asn370Ser) (rs777511615)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569917 SCV000668877 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-05 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000569917 SCV000689247 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586091 SCV000699659 uncertain significance not provided 2017-06-05 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.1109A>G (p.Asn370Ser) variant located in the P-loop containing nucleoside triphosphate hydrolase domain (via InterPro) involves the alteration of a conserved nucleotide and 2/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 1/122506 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625). Multiple publications have cited the variant in affected cohorts, however, limited information is available (ie, lack of co-occurrence and cosegregation data). The variant of interest has not, to our knowledge, been reported by reputable databases/clinical diagnostic laboratories. Therefore, until additional information becomes available, ie, clinical and functional studies, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Counsyl RCV000662391 SCV000784800 uncertain significance Fanconi anemia, complementation group J; Neoplasm of ovary 2017-01-17 criteria provided, single submitter clinical testing
Invitae RCV001069949 SCV001235149 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group J 2019-11-28 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 370 of the BRIP1 protein (p.Asn370Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs777511615, ExAC 0.001%). This variant has been observed in an individual affected with ovarian cancer and an individual affected with head and neck cancer (PMID: 24448499, 28678401). ClinVar contains an entry for this variant (Variation ID: 483144). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Illumina Clinical Services Laboratory,Illumina RCV001124865 SCV001283869 uncertain significance Fanconi anemia, complementation group J 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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