rs587780646
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000059.4(BRCA2):āc.1838T>Gā(p.Leu613Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,607,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L613V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.1838T>G | p.Leu613Arg | missense_variant | 10/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.1838T>G | p.Leu613Arg | missense_variant | 10/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000264 AC: 4AN: 151494Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000703 AC: 17AN: 241692Hom.: 0 AF XY: 0.0000305 AC XY: 4AN XY: 131344
GnomAD4 exome AF: 0.0000124 AC: 18AN: 1455558Hom.: 0 Cov.: 35 AF XY: 0.00000553 AC XY: 4AN XY: 723852
GnomAD4 genome ? AF: 0.0000264 AC: 4AN: 151494Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 73944
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 12, 2022 | 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. - |
Likely benign, criteria provided, single submitter | curation | University of Washington Department of Laboratory Medicine, University of Washington | Mar 23, 2023 | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 03, 2017 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 31, 2016 | - - |
Likely benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Sep 11, 2013 | - - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 11, 2023 | The frequency of this variant in the general population, 0.00051 (17/33368 chromosomes in Latino/Admixed American subpop subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, this variant has been reported in an individual affected with breast cancer (PMID: 12442275 (2002)). In addition, this variant has been identified in the somatic state in colorectal tumor samples (PMIDs: 28591715 (2017) and 33054725 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 25, 2021 | This variant is associated with the following publications: (PMID: 12442275, 28591715, 24817641) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 19, 2024 | Variant summary: BRCA2 c.1838T>G (p.Leu613Arg) results in a non-conservative amino acid change in 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 7.4e-05 in 241822 control chromosomes, predominantly at a frequency of 0.00051 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (7.4e-05 vs 0.00075), allowing no conclusion about variant significance. c.1838T>G has been reported in the literature in one Latino (Mexican) patient with breast cancer who had positive family history of breast (a sister and a paternal cousin) and other cancers (leukemia and prostate cancer) (Ruiz-Flores_2002), in a cohort of patients with MSI-high colorectal cancer (Deihimi_2017), and in a prostate cancer patient without strong evidence for causality (Giri_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12442275, 28591715, 35666082). ClinVar contains an entry for this variant (Variation ID: 135791). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
BRCA2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 22, 2024 | The BRCA2 c.1838T>G variant is predicted to result in the amino acid substitution p.Leu613Arg. This variant (also reported as c.2066T>G) has been observed in a Latino individual with breast cancer who also had a family history of prostate cancer and leukemia (Ruiz-Flores et al. 2002. PubMed ID: 12442275). This variant is reported in 0.051% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/135791/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Leu613Arg variant was identified in 1 of 64 proband chromosomes (frequency: 0.02) from individuals or families with breast cancer and was present in 1 of 130 control chromosomes (frequency: 0.008) from healthy individuals (Ruiz-Flores 2002). The variant was also identified in dbSNP (ID: rs587780646) as "With other allele" and ClinVar (classified as likely benign by SCRP and GeneDx; and as uncertain significance by Invitae, Ambry Genetics and three other submitters). The variant was not identified in LOVD 3.0 or UMD-LSDB. The variant was identified in control databases in 17 of 236466 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the Latino population in 17 of 32544 chromosomes (freq: 0.0005), while the variant was not observed in the African, Other, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Leu613 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 summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at