13-32398583-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000059.4(BRCA2):​c.10070C>T​(p.Thr3357Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 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. T3357A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

BRCA2
NM_000059.4 missense

Scores

16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 0.642
Variant links:
Genes affected
BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.058388233).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRCA2NM_000059.4 linkuse as main transcriptc.10070C>T p.Thr3357Ile missense_variant 27/27 ENST00000380152.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA2ENST00000380152.8 linkuse as main transcriptc.10070C>T p.Thr3357Ile missense_variant 27/275 NM_000059.4 A2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152150
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152150
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingCounsylJan 30, 2017- -
Uncertain significance, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA2)-- -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 20, 2023The p.T3357I variant (also known as c.10070C>T), located in coding exon 26 of the BRCA2 gene, results from a C to T substitution at nucleotide position 10070. The threonine at codon 3357 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 06, 2016- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 03, 2017Variant summary: The BRCA2 c.10070C>T (p.Thr3357Ile) variant involves the alteration of a non-conserved nucleotide that leads to change in an evolutionarily non-conserved amino acid residue that is located at the C-terminal end of the protein that does not belong to any known functional domain. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). In addition, a truncation variant upstream of this position have been observed in the general population (with several homozygous occurrences) and classified as benign by our laboratory and others (c.9976A>T (p.Lys3326Ter)), suggesting that even the complete functional loss of this C-terminal protein part wouldnt lead to deleterious biological effects, though these predictions have not been confirmed by in vitro or in vivo functional studies. This variant was found in 1/30974 control chromosomes at a frequency of 0.0000323, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 15, 2014This variant is denoted BRCA2 c.10070C>T at the cDNA level, p.Thr3357Ile (T3357I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant was observed at least once in an individual whose personal and/or family history was presumably suspicious for hereditary breast and ovarian cancer syndrome (Olopade 2003). BRCA2 Thr3357Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Thr3357Ile occurs at a position that is variable across species and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Thr3357Ile is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 20, 2022This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 3357 of the BRCA2 protein (p.Thr3357Ile). This variant is present in population databases (rs80358388, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 51036). 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. 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.086
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.70
CADD
Benign
14
DANN
Benign
0.94
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.12
N
M_CAP
Benign
0.035
D
MetaRNN
Benign
0.058
T;T
MetaSVM
Benign
-0.93
T
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.23
T
PROVEAN
Benign
-0.68
N;N
REVEL
Benign
0.043
Sift
Benign
0.19
T;T
Sift4G
Benign
0.38
T;T
Vest4
0.076
MutPred
0.17
Loss of disorder (P = 0.0495);Loss of disorder (P = 0.0495);
MVP
0.62
MPC
0.027
ClinPred
0.039
T
GERP RS
2.2
gMVP
0.065

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80358388; hg19: chr13-32972720; API