chr17-43090997-C-T
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_007294.4(BRCA1):c.4132G>A(p.Val1378Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,612,732 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1378A) has been classified as Uncertain significance.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.4132G>A | p.Val1378Ile | missense_variant | 11/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.4132G>A | p.Val1378Ile | missense_variant | 11/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000401 AC: 61AN: 152132Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000173 AC: 43AN: 249014Hom.: 1 AF XY: 0.000201 AC XY: 27AN XY: 134562
GnomAD4 exome AF: 0.0000705 AC: 103AN: 1460600Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 49AN XY: 726488
GnomAD4 genome ? AF: 0.000401 AC: 61AN: 152132Hom.: 1 Cov.: 32 AF XY: 0.000498 AC XY: 37AN XY: 74312
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:4
Benign, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Mar 24, 1999 | - - |
Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Jun 18, 2019 | 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 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 22, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not provided Benign:4
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 27, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2022 | BRCA1: BP4, BS1, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2020 | This variant is associated with the following publications: (PMID: 15385441, 30675319, 23867111, 15235020, 16826315, 24607278, 23982851, 25777348, 16267036, 26689913, 23704879, 32438681) - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 08, 2022 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 08, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 08, 2019 | 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. - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 27, 2022 | - - |
Breast and/or ovarian cancer Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Oct 06, 2021 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Jun 25, 2014 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 01, 2021 | 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. - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at