chr13-32339526-T-C
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_000059.4(BRCA2):āc.5171T>Cā(p.Ile1724Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,451,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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. I1724V) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.5171T>C | p.Ile1724Thr | missense_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.5171T>C | p.Ile1724Thr | missense_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000276 AC: 4AN: 1451230Hom.: 0 Cov.: 45 AF XY: 0.00000139 AC XY: 1AN XY: 721858
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 17, 2018 | 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 | Jun 13, 2018 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 19, 2016 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 04, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 14, 2020 | This variant is associated with the following publications: (PMID: 24817641, 26295337, 30212499, 28301460, 29906251) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 06, 2024 | Variant summary: BRCA2 c.5171T>C (p.Ile1724Thr) 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 was absent in 244828 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5171T>C has been reported in the literature in individuals affected with lung cancer and esophageal squamous cell carcinoma (e.g., Pietanza_2018, Ko_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Several publications have performed prediction analyses to classify the variant using several methods which incorporate data from probability of pathogenicity calculations and/or in silico tools, and have classified the variant as likely benign (e.g., Padilla_2019, Cline_2019, Parsons_2019). However, 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: 31294896, 24817641, 28301460, 31396961, 31112341, 31131967, 29906251). ClinVar contains an entry for this variant (Variation ID: 51803). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Ile1724Thr variant has been previously reported in the BIC database with unknown clinical significance in three individuals; it has also been identified in one individual with a clinical history of breast/ovarian cancer by our laboratory. This residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. This variant is listed in dbSNP with no frequency information (ID#:rs80358743). Another variant at the same amino acid position (c.5170A>G p.Ile1724Val) is listed as a polymorphism in dbSNP rs35335654 with an average heterozygosity of 0.027+/-0.112, increasing the likelihood the p.Ile1724Thr variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty although we would lean towards a more benign role for this variant. This variant is classified as Predicted Benign. - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at