rs397507436
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_000059.4(BRCA2):āc.9812T>Cā(p.Leu3271Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L3271F) has been classified as Uncertain significance.
Frequency
Consequence
NM_000059.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.9812T>C | p.Leu3271Ser | missense_variant | 27/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.9812T>C | p.Leu3271Ser | missense_variant | 27/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251370Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135868
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461870Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727236
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74326
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 25, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 05, 2016 | This variant is denoted BRCA2 c.9812T>C at the cDNA level, p.Leu3271Ser (L3271S) at the protein level, and results in the change of a Leucine to a Serine (TTG>TCG). Using alternate nomenclature, this variant would be defined as BRCA2 10040T>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Leu3271Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Leu3271Ser occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is located within the Cyclin A binding domain (Esashi 2005). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Leu3271Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 22, 2019 | Variant summary: BRCA2 c.9812T>C (p.Leu3271Ser) results in a non-conservative amino acid change located in the Cy (RxL)-binding motif (amino acids 3,269-3,271; Esashi_2005) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251370 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9812T>C has been reported in the literature in an individual affected with Breast Cancer (Tung_2015). This report does not provide an unequivocal conclusion about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Oct 16, 2012 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 05, 2022 | The p.L3271S variant (also known as c.9812T>C), located in coding exon 26 of the BRCA2 gene, results from a T to C substitution at nucleotide position 9812. The leucine at codon 3271 is replaced by serine, an amino acid with dissimilar properties. This variant was observed in an individual with early onset-breast cancer amongst a cohort of 1781 non-Ashkenazi Jewish individuals undergoing BRCA1/2 gene testing based on a personal history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 3271 of the BRCA2 protein (p.Leu3271Ser). This variant is present in population databases (rs397507436, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 38264). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at