ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1036C>T (p.Pro346Ser) (rs80357015)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000030970 SCV001161569 benign Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00281 (East Asian), derived from gnomAD v2.1.1 non-cancer (2019-05-13).
Invitae RCV001079175 SCV000075328 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130509 SCV000185378 likely benign Hereditary cancer-predisposing syndrome 2019-04-03 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
GeneDx RCV000047315 SCV000209919 likely benign not specified 2017-05-30 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000047315 SCV000586877 likely benign not specified 2017-04-18 criteria provided, single submitter clinical testing
Counsyl RCV000030970 SCV000785447 uncertain significance Breast-ovarian cancer, familial 1 2017-08-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130509 SCV000902944 benign Hereditary cancer-predisposing syndrome 2016-10-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000047315 SCV000916714 likely benign not specified 2019-04-12 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1036C>T (p.Pro346Ser) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 277056 control chromosomes, predominantly at a frequency of 0.0026 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.1036C>T, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Kuo_2012, Sun_2014, Thirthagiri_2008, Flower_2015, Chao_2016, Lai_2017, Chan_2018). Thus, these reports 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1x VUS, 3x likely benign, 1X benign). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000195311 SCV001133475 benign not provided 2019-03-12 criteria provided, single submitter clinical testing
Mendelics RCV000030970 SCV001140612 benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000030970 SCV000053561 benign Breast-ovarian cancer, familial 1 2012-02-13 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000030970 SCV000143987 uncertain significance Breast-ovarian cancer, familial 1 2010-09-18 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357043 SCV001552371 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Pro346Ser variant was identified in 3 of 482 proband chromosomes (frequency: 0.006) from Taiwanese and Malaysian individuals or families with breast cancer, early onset breast cancer or a family history of breast and ovarian cancer (Li 1999, Kuo 2012, Thirthagiri 2008). In these studies, the variant was considered a polymorphism, found to co-occur with a pathogenic BRCA2 mutation (exon 3: 490 delCT/STOP 99) in one proband and linkage was not established in another. The variant was also identified in dbSNP (ID: rs80357015) “With other allele”, ClinVar (classified with conflicting interpretations of pathogenicity; benign by Invitae and SCRP (Sharing Clinical Reports Project); likely benign by Ambry Genetics and GeneDx; and uncertain significance by BIC)), Clinvitae (5X), LOVD 3.0 (2x), UMD-LSDB (2-Likely Neutral), BIC Database (4X, unknown clinical importance, classification pending), and Zhejiang Colon Cancer Database (2x); but was not identified in COGR, Cosmic, MutDB, and ARUP Laboratories databases. The variant was identified in control databases in 49 of 276996 chromosomes at a frequency of 0.0002 in the following population: East Asian in 49 of 18868 chromosomes (freq. 0.0025), increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Pro346 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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