ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4046C>T (p.Thr1349Met) (rs80357345)

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Total submissions: 9
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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) RCV000077561 SCV000244352 benign Breast-ovarian cancer, familial 1 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000442
Invitae RCV000195392 SCV000076435 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-24 criteria provided, single submitter clinical testing
GeneDx RCV000048422 SCV000209966 likely benign not specified 2017-07-28 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.
Ambry Genetics RCV000162981 SCV000213469 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048422 SCV000699102 likely benign not specified 2019-04-09 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4046C>T (p.Thr1349Met) results in a non-conservative amino acid change in 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 2.3e-05 in 301778 control chromosomes (gnomAD and publication). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4046C>T has been reported in the literature in individual(s) from hereditary breast/ovarian cancer families (Judkins_2005) and an individual affected with Medulloblastoma who also carried a pathogenic variant in the APC gene (c.2805C>G, p.Y935*) (Zhang_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. The variant has been reported in the FLOSSIES database in one woman older than age 70 years who has never had cancer while, it was also reported by Momozawa et al (2018) in one control 60 years old or over with no past history nor family history of cancers; these data provide supporting evidence for a benign role of the variant. Furthermore, databases (LOVD, UMD) and peer-reviewed studies (Momozawa_2018, Zhang_2015, Easton_2007) classify this variant as likely benign/benign/neutral. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign while, a submission from an expert panel (ENIGMA) cites the variant as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Color Health, Inc RCV000162981 SCV000912032 likely benign Hereditary cancer-predisposing syndrome 2016-11-14 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077561 SCV000109363 uncertain significance Breast-ovarian cancer, familial 1 2007-12-11 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077561 SCV000144946 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353924 SCV000591483 likely benign not provided no assertion criteria provided clinical testing The BRCA1 p.Thr1349Met variant was identified in 4 of 113500 proband chromosomes (frequency: 0.00004) from individuals or families with breast or ovarian cancer (Zhang 2015, Judkins 2005). The variant was also identified in dbSNP (ID: rs80357345) as "With Uncertain significance, other allele", ClinVar (classified as benign by ENIGMA and Ambry Genetics; as likely benign by Invite and GeneDx; as uncertain significance by four submitters), COGR, Cosmic (1x in Large intestine tissue), MutDB, LOVD 3.0 (4x), UMD-LSDB (3x as likely neutral), BIC Database (3x with unknown significance), and in ARUP Laboratories (not pathogenic or of no clinical significance). The variant was not identified in Zhejiang University Database. The variant was identified in control databases in 6 of 276798 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African population in 6 of 24028 chromosomes (freq: 0.0003); it was not observed in the Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Thr1349 residue is not 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In Multifactorial probability-based model and Systematic Genetic Assessment for classification the variant was found to have posterior probability of being deleterious -4.42 × 10–5 with odds in favor of neutrality 462 (Lindor 2011, Easton 2007). In addition, this variant has been reported in one individual from our laboratory who had a second pathogenic variant in the BRCA2 gene (c.9097dupA, p.Thr3033AsnfsX11), increasing the likelihood that the p.Thr1349Met variant does not have clinical significance. 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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