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

gnomAD frequency: 0.00017  dbSNP: rs28897690

Total submissions: 18

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195345	SCV000076469	benign	Hereditary breast ovarian cancer syndrome	2025-02-02	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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
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 Diagnostics, LLC DBA Color Health	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, part of Exact Sciences	RCV000588834	SCV000806945	likely benign	not provided	2017-03-27	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
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735522	SCV003838899	likely benign	Breast and/or ovarian cancer	2021-10-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588834	SCV004140624	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	BRCA1: BP4, BS1, BS2
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588834	SCV004219392	benign	not provided	2022-09-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004803994	SCV004817703	likely benign	BRCA1-related cancer predisposition	2024-09-23	criteria provided, single submitter	clinical testing
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
BRCAlab, Lund University	RCV000112269	SCV004244004	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing