13-32339586-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000059.4(BRCA2):​c.5231G>T​(p.Ser1744Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,610,478 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).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

2
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:3

Conservation

PhyloP100: -0.785
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.070795).
BP6
Variant 13-32339586-G-T is Benign according to our data. Variant chr13-32339586-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141853.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=7}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA2NM_000059.4 linkc.5231G>T p.Ser1744Ile missense_variant Exon 11 of 27 ENST00000380152.8 NP_000050.3 P51587

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkc.5231G>T p.Ser1744Ile missense_variant Exon 11 of 27 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.4862G>T p.Ser1621Ile missense_variant Exon 11 of 27 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.5231G>T non_coding_transcript_exon_variant Exon 10 of 26 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152134
Hom.:
0
Cov.:
33
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:
0.000385
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000241
AC:
6
AN:
249282
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
134832
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000327
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1458344
Hom.:
0
Cov.:
44
AF XY:
0.00000276
AC XY:
2
AN XY:
725542
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152134
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000385
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2Benign:1
Dec 28, 2015
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 03, 2023
Myriad Genetics, Inc.
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Oct 06, 2023
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces serine with isoleucine at codon 1744 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with lymphoma, breast, ovarian, and colorectal cancer (PMID: 23960188, 27907908, 28664449, 32548945). In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 6/60466 cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007158). This variant has been identified in 7/280688 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Sep 20, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces serine with isoleucine at codon 1744 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with lymphoma, breast, ovarian, and colorectal cancer (PMID: 23960188, 27907908, 28664449, 32548945). In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 6/60466 cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_007158). This variant has been identified in 7/280688 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Mar 23, 2023
University of Washington Department of Laboratory Medicine, University of Washington
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

Aug 04, 2022
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Uncertain:1
Aug 25, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1
Jul 13, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: BRCA2 c.5231G>T (p.Ser1744Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 249282 control chromosomes, exclusively within the East Asian subpopulation in the gnomAD database at a frequency of 0.00033. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5231G>T has been reported in the literature in individuals affected with breast cancer (e.g. Li_2017, Tria_2019), ovarian cancer (e.g. Chao_2016), Lynch Syndrome (e.g. Xu_2020), and DLBCL (e.g. deMiranda_2013). These publications do not report strong evidence for causality and thus 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. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1
Nov 27, 2019
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1
Nov 10, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1744 of the BRCA2 protein (p.Ser1744Ile). This variant is present in population databases (rs587782060, gnomAD 0.04%). This missense change has been observed in individual(s) with breast, ovarian cancer and colorectal cancer (PMID: 27907908, 28664449, 32548945). ClinVar contains an entry for this variant (Variation ID: 141853). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
9.1
DANN
Benign
0.97
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.053
N
M_CAP
Benign
0.038
D
MetaRNN
Benign
0.071
T;T
MetaSVM
Benign
-0.91
T
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-2.2
N;N
REVEL
Benign
0.19
Sift
Uncertain
0.017
D;D
Sift4G
Uncertain
0.034
D;D
Vest4
0.29
MutPred
0.26
Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP
0.76
MPC
0.032
ClinPred
0.037
T
GERP RS
-3.8
gMVP
0.16

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: rs587782060; hg19: chr13-32913723; COSMIC: COSV105932258; API