ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4132G>A (p.Val1378Ile)

gnomAD frequency: 0.00017  dbSNP: rs28897690
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Total submissions: 14
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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) RCV000112269 SCV001161590 benign Breast-ovarian cancer, familial, susceptibility to, 1 2019-06-18 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 = 0.000026
Invitae RCV000195345 SCV000076469 benign Hereditary breast ovarian cancer syndrome 2021-11-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130952 SCV000185866 likely benign Hereditary cancer-predisposing syndrome 2019-03-08 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
GeneDx RCV000588834 SCV000210168 likely benign not provided 2020-09-08 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 15385441, 30675319, 23867111, 15235020, 16826315, 24607278, 23982851, 25777348, 16267036, 26689913, 23704879, 32438681)
Counsyl RCV000112269 SCV000488205 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2016-01-22 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130952 SCV000683154 likely benign Hereditary cancer-predisposing syndrome 2015-06-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048456 SCV000699111 benign not specified 2021-11-01 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4132G>A (p.Val1378Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 249014 control chromosomes, predominantly at a frequency of 0.00099 within the Latino subpopulation in the gnomAD database, including 1 homozygote. This frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00099 vs 0.001), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. The variant, c.4132G>A, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Judkins_2005, Andres_2014, Machackova_2019, Santonocito_2020, Dorling_2021) but it was also reported in unaffected controls (Dorling_2021). The variant of interest was identified in several sporadic breast cancer cases but it did not segregate with the disease in a large HBOC family (Santos_2014). Co-occurrences with pathogenic variants have been reported (BRCA2 c.2701delC, p.Ala902LeufsX2; BRCA2 c.5763delT, p.Phe1921LeufsX42; BRCA1 c.5335delC, p.Gln1779AsnfsX14; UMD and Internal testing), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function demonstrated the variant to confer similar activity to wild-type (Bouwman_2013, Lu_2015). Nine ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as benign/likely benign while one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. A recent publication involving the ENIGMA network of collaborators (Parsons_2019) assigned a classification of benign based on likelihood ratios (LRs) for pathogenicity estimated from clinical data of co-segregation with disease, co-occurrence with a pathogenic variant, reported family history, breast tumor pathology and bioinformatic predictions. Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics,PreventionGenetics RCV000588834 SCV000806945 likely benign not provided 2017-03-27 criteria provided, single submitter clinical testing
Mendelics RCV000195345 SCV000839241 likely benign Hereditary breast ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000112269 SCV001140535 likely benign Breast-ovarian cancer, familial, susceptibility to, 1 2019-05-28 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000130952 SCV002538267 benign Hereditary cancer-predisposing syndrome 2022-01-27 criteria provided, single submitter curation
Breast Cancer Information Core (BIC) (BRCA1) RCV000112269 SCV000144995 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 1999-03-24 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353555 SCV000591495 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Val1378Ile variant was identified in 3 of 700 proband chromosomes (frequency: 0.004) from individuals or families with breast or ovarian cancer (Peixoto 2006, El Saghir 2015). The variant was also identified in dbSNP (ID: rs28897690) as "With Uncertain significance allele", ClinVar (classified as benign by Invitae; as likely benign by Ambry Genetics, GeneDx, COGR, Color Genomics and two clinical laboratories; as uncertain significance by BIC), Cosmic (1x in Central nervous system), LOVD 3.0 (8x ), UMD-LSDB (9x as unclassified variant), and in BIC Database (3x with unknown clinical significance). In UMD the variant was identified with a co-occurring pathogenic BRCA2 variants (c.2701delC, p.Ala902LeufsX2) or (c.5763delT, p.Phe1921LeufsX42), increasing the likelihood that the p.Val1378Ile variant does not have clinical significance. The variant was not identified in MutDB, ARUP Laboratories, or Zhejiang University databases. The variant was identified in control databases in 49 of 274850 chromosomes (1 homozygous) at a frequency of 0.0002 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: Other in 1 of 6406 chromosomes (freq: 0.0002), Latino in 35 of 34190 chromosomes (freq: 0.001), European in 10 of 125746 chromosomes (freq: 0.00008), East Asian in 1 of 18824 chromosomes (freq: 0.00005), and South Asian in 2 of 30406 chromosomes (freq: 0.00007), while the variant was not observed in the African, Ashkenazi Jewish, or Finnish, populations. The p.Val1378 residue is not conserved in mammals and 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) do not predict a difference in splicing. In addition, this variant was classified by several functional and in silico studies where it was classified once as “likely neutral” (Abkevich 2004), twice as “neutral” (Bouwman 2013, Santos 2014) and once as “unknown” (Judkins 2005). 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.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735522 SCV000863660 uncertain significance Breast and/or ovarian cancer 2014-06-25 no assertion criteria provided clinical testing

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