ClinVar Miner

Submissions for variant NM_032043.3(BRIP1):c.2220G>T (p.Gln740His)

gnomAD frequency: 0.00041  dbSNP: rs45589637
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Total submissions: 26
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123354 SCV000166677 likely benign Familial cancer of breast; Fanconi anemia complementation group J 2021-12-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131414 SCV000186392 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-20 criteria provided, single submitter clinical testing The p.Q740H variant (also known as c.2220G>T), located in coding exon 14 of the BRIP1 gene, results from a G to T substitution at nucleotide position 2220. The glutamine at codon 740 is replaced by histidine, an amino acid with highly similar properties. This alteration has been observed in several studies: in 1/681 individuals in a healthy, ancestrally diverse cohort, in 5/3236 serous ovarian cases and 1/3431 controls, in a breast and/or ovarian cancer family that previously tested negative for mutations in the BRCA1/2 genes, and a Lebanese familial breast cancer case (Bodian DL et al. PLoS ONE. 2014 Apr;9:e94554; Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107; Li J et al. J. Med. Genet. 2016 Jan;53:34-42; Jalkh N et al. BMC Med Genomics. 2017 02;10:8). Additional studies have identified this variant in individuals with early onset colon cancer and pancreatic cancer (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471; Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000488342 SCV000210815 likely benign not provided 2020-07-28 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28202063, 31159747, 25980754, 24728327, 26534844, 27547810, 26315354, 28528518, 26921362, 27978560, 28678401, 28767289, 31822495, 32039725, 31658756, 33115781)
Counsyl RCV000409608 SCV000489867 uncertain significance Fanconi anemia complementation group J 2016-08-23 criteria provided, single submitter clinical testing
Counsyl RCV000411134 SCV000489868 uncertain significance Neoplasm of ovary 2016-08-23 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000488342 SCV000575119 uncertain significance not provided 2017-01-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000120396 SCV000593775 uncertain significance not specified 2016-04-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000488342 SCV000699683 likely benign not provided 2016-09-02 criteria provided, single submitter clinical testing Variant summary: The BRIP1 c.2220G>T (p.Gln740His) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 58/133810 control chromosomes at a frequency of 0.0004335, which is approximately 7 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this variant is likely a benign polymorphism. This variant has been reported in multiple cancer patients, however, a case-control study showed that this variant was not associated with breast cancer (OR=0.638, P=0.49, Haiman_2013). In addition, two patients carry the variant of interest and a pathogenic variant, homozygous MUTYH c.1187G>A/p.Gly396Asp and PALB2 c.3113G>A/W1038X, respectively (Yurgelun_2015, Kahn_2016), suggesting the variant of interest may be benign. On the other hand, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000488342 SCV000807127 uncertain significance not provided 2017-04-06 criteria provided, single submitter clinical testing
GeneKor MSA RCV000131414 SCV000821956 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000409608 SCV000839371 uncertain significance Fanconi anemia complementation group J 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000488342 SCV000889209 likely benign not provided 2020-10-22 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131414 SCV000910572 likely benign Hereditary cancer-predisposing syndrome 2020-11-20 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000778128 SCV000914253 uncertain significance BRIP1-Related Disorders 2019-04-05 criteria provided, single submitter clinical testing The BRIP1 c.2220G>T (p.Gln740His) missense variant has been reported in at least four studies in which it is found in a heterozygous state in total of three individuals with Lynch syndrome, one of whom also carried a homozygous variant in the MUTYH gene (Bodian et al. 2014; Ramus et al. 2015; Yurgelun et al. 2015; Easton et al. 2016). The p.Gln740His variant was identified in a heterozygous state in six of 3431 controls and is reported at a frequency of 0.00140 in the Latino population of the Genome Aggregation Database. Based on the limited evidence, the p.Gln740His variant is classified as a variant of unknown significance but suspicious for pathogenicity for BRIP1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Mendelics RCV000989999 SCV001140761 uncertain significance Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000409608 SCV001368803 uncertain significance Fanconi anemia complementation group J 2019-03-18 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP1.
Institute of Human Genetics, University of Leipzig Medical Center RCV000989999 SCV001440914 uncertain significance Familial cancer of breast 2019-01-01 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000989999 SCV002010917 uncertain significance Familial cancer of breast 2021-11-03 criteria provided, single submitter clinical testing
Baylor Genetics RCV000409608 SCV002030141 uncertain significance Fanconi anemia complementation group J 2021-02-09 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001798382 SCV002043627 uncertain significance Breast and/or ovarian cancer 2021-01-27 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000488342 SCV002050046 likely benign not provided 2020-10-08 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000989999 SCV002512662 uncertain significance Familial cancer of breast 2021-06-15 criteria provided, single submitter clinical testing ACMG classification criteria: BS1 strong
Sema4,Sema4 RCV000131414 SCV002531397 likely benign Hereditary cancer-predisposing syndrome 2021-04-11 criteria provided, single submitter curation
ITMI RCV000120396 SCV000084548 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000131414 SCV000805252 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-09 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358098 SCV001553749 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRIP1 p.Gln740His variant was identified in 32 of 48608 proband chromosomes (frequency: 0.0007) from individuals or families with breast, ovarian cancer or Lynch syndrome and was present in 7 of 14818 control chromosomes (frequency: 0.0006) from healthy individuals (Easton 2016, Jalkh 2017, Li 2015, Penkert 2018, Ramus 2015, Tung 2015, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs45589637) as "With other allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and nine other submitters; as likely benign by Integrated Genetics/Laboratory Corporation of America and GeneDx). The variant was identified in control databases in 144 of 277004 chromosomes at a frequency of 0.0005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24024 chromosomes (freq: 0.00008), Other in 4 of 6460 chromosomes (freq: 0.0006), Latino in 48 of 34414 chromosomes (freq: 0.001), European in 82 of 126532 chromosomes (freq: 0.0007), Ashkenazi Jewish in 2 of 10148 chromosomes (freq: 0.0002), Finnish in 6 of 25780 chromosomes (freq: 0.0002); it was not observed in the East Asian, and South Asian populations. The p.Gln740 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 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of 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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