ClinVar Miner

Submissions for variant NM_032043.3(BRIP1):c.415T>G (p.Ser139Ala)

gnomAD frequency: 0.00004  dbSNP: rs202072866
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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000119157 SCV000153877 uncertain significance Familial cancer of breast; Fanconi anemia complementation group J 2024-01-28 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 139 of the BRIP1 protein (p.Ser139Ala). This variant is present in population databases (rs202072866, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer and/or colorectal cancer (PMID: 18414782, 26534844, 26921362, 28135145, 30262796, 34646395). ClinVar contains an entry for this variant (Variation ID: 132712). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRIP1 protein function with a negative predictive value of 80%. 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.
Ambry Genetics RCV000131152 SCV000186094 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-02 criteria provided, single submitter clinical testing The p.S139A variant (also known as c.415T>G), located in coding exon 4 of the BRIP1 gene, results from a T to G substitution at nucleotide position 415. The serine at codon 139 is replaced by alanine, an amino acid with similar properties. This variant has been reported in patients with breast cancer in several studies (Guénard F et al. J. Hum. Genet. 2008 Apr;53:579-91; Laraqui A et al. J Genomics, 2021 Sep;9:43-54; Li J et al. J. Med. Genet. 2016 Jan;53:34-42; Easton DF et al. J. Med. Genet. 2016 May;53:298-309; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). However, this variant was reported in 5/60,466 breast cancer cases and in 3/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Additionally, in a study of ovarian cancer patients, this variant was not seen in 3236 cases but was observed in 1/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is tolerated. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000589911 SCV000278893 uncertain significance not provided 2022-12-13 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer and in an individual with colorectal cancer, but also observed in a healthy control (Gunard et al., 2008; Lu et al., 2015; Ramus et al., 2015; Easton et al., 2016; Li et al., 2016; Yurgelun et al., 2017; Quezada Urban et al., 2018; Moyer et al., 2020; Laraqui et al., 2021); This variant is associated with the following publications: (PMID: 18414782, 26315354, 26534844, 26689913, 26921362, 28135145, 19197335, 30262796, 31159747, 31822495, 33471991, 34646395)
Counsyl RCV000411415 SCV000489997 uncertain significance Fanconi anemia complementation group J 2016-09-13 criteria provided, single submitter clinical testing
Counsyl RCV000412061 SCV000489998 uncertain significance Neoplasm of ovary 2016-09-13 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131152 SCV000684279 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-16 criteria provided, single submitter clinical testing This missense variant replaces serine with alanine at codon 139 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 18414782, 26534844, 26921362, 33471991, 34646395) and colorectal cancer (PMID:28135145) in the literature. It has also been observed in control individuals (PMID: 26315354, 33471991). This variant has been identified in 12/282614 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001800405 SCV000699707 uncertain significance not specified 2022-02-02 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.415T>G (p.Ser139Ala) results in a conservative amino acid change located in the Helicase-like, DEXD box c2 type domain (IPR006554) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 258216 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRIP1 causing Hereditary Breast And Ovarian Cancer Syndrome (4.6e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.415T>G has been reported in the literature as a VUS in settings of multigene panel testing among individuals with breast/colorectal cancers (example, Guenard_2008, Li_2015, Zick_2015, Yurgelun_2017, Quezada_2018, Tsaousis_2019, Dorling_2021) and unaffected controls (example, Ramus_2015, Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome/Fanconi Anemia Complementation Group J. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneKor MSA RCV000131152 SCV000821965 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000411415 SCV000839399 uncertain significance Fanconi anemia complementation group J 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000990035 SCV001140799 uncertain significance Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000411415 SCV001287321 uncertain significance Fanconi anemia complementation group J 2017-04-28 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000589911 SCV002010903 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001800405 SCV002046616 uncertain significance not specified 2021-01-28 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000131152 SCV002533709 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-24 criteria provided, single submitter curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000990035 SCV002584592 uncertain significance Familial cancer of breast 2022-08-30 criteria provided, single submitter clinical testing The BRIP1 c.415T>G (p.Ser139Ala) missense change has a maximum subpopulation frequency of 0.0078% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 26534844, 31159747, 34646395). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the role of this variant in disease. It has therefore been classified as of uncertain significance.
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV000990035 SCV003936123 uncertain significance Familial cancer of breast 2023-07-04 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 139 of the BRIP1 protein (p.Ser139Ala). This variant is present in population databases (rs202072866, gnomAD 0.008%). This amino acid position is not highly conserved (PhyloP=5.5 ). This missense change has been observed in individual(s) with breast cancer and/or colorectal cancer (PMID: 18414782, 26534844, 26921362, 28135145, 30262796). ClinVar contains an entry for this variant (Variation ID: 132712). 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: "Possibly Damaging"). 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.
Myriad Genetics, Inc. RCV000990035 SCV004019478 uncertain significance Familial cancer of breast 2023-03-02 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics RCV000990035 SCV004214612 uncertain significance Familial cancer of breast 2023-10-29 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355891 SCV001550905 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRIP1 p.Ser139Ala variant was identified in 4 of 34276 proband chromosomes (frequency: 0.0001) from individuals or families with ovarian and breast cancer, and was present in 1 of 17488 control chromosomes (frequency: 0.0001) from healthy individuals (Beltrame 2015, Li 2015, Easton 2016, Guenard 2008, Ramus 2015). The variant was also identified in the following databases: dbSNP (ID: rs202072866) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx, Counsyl, Color Genomics), and Cosmic (classified as pathogenic). The variant was not identified in the MutDB database or Zhejiang Colon Cancer Database. The variant was identified in control databases in 12 of 276988 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 1 of 6462 chromosomes (freq: 0.0002), Latino in 1 of 34404 chromosomes (freq: 0.00003), European Non-Finnish in 10 of 126542 chromosomes (freq: 0.0001), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Ser139 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume 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.

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