chr13-32338416-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong

The NM_000059.4(BRCA2):​c.4061C>T​(p.Thr1354Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,604,652 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 Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. T1354T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

1
2
13

Clinical Significance

Benign reviewed by expert panel U:1B:25O:1

Conservation

PhyloP100: 0.161
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 Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.078579396).
BP6
Variant 13-32338416-C-T is Benign according to our data. Variant chr13-32338416-C-T is described in ClinVar as [Benign]. Clinvar id is 51588.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338416-C-T is described in Lovd as [Benign]. Variant chr13-32338416-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA2NM_000059.4 linkc.4061C>T p.Thr1354Met 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.4061C>T p.Thr1354Met missense_variant Exon 11 of 27 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.3692C>T p.Thr1231Met missense_variant Exon 11 of 27 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.4061C>T non_coding_transcript_exon_variant Exon 10 of 26 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
151998
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000484
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000140
AC:
34
AN:
243546
Hom.:
0
AF XY:
0.000160
AC XY:
21
AN XY:
131438
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000123
Gnomad ASJ exome
AF:
0.000515
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000356
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000197
Gnomad OTH exome
AF:
0.000336
GnomAD4 exome
AF:
0.000120
AC:
175
AN:
1452654
Hom.:
0
Cov.:
35
AF XY:
0.000125
AC XY:
90
AN XY:
721722
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000234
Gnomad4 ASJ exome
AF:
0.000658
Gnomad4 EAS exome
AF:
0.000304
Gnomad4 SAS exome
AF:
0.0000481
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000100
Gnomad4 OTH exome
AF:
0.000283
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
151998
Hom.:
0
Cov.:
33
AF XY:
0.0000808
AC XY:
6
AN XY:
74248
show subpopulations
Gnomad4 AFR
AF:
0.0000484
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000225
Hom.:
0
Bravo
AF:
0.000136
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000124
AC:
15

ClinVar

Significance: Benign
Submissions summary: Uncertain:1Benign:25Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:7
May 28, 2019
Mendelics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 20, 2004
Breast Cancer Information Core (BIC) (BRCA2)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 09, 2014
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 12, 2014
Counsyl
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: literature only

- -

May 01, 2012
Sharing Clinical Reports Project (SCRP)
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 21, 2015
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 10, 2015
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance: Benign
Review Status: reviewed by expert panel
Collection Method: curation

IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000803 -

not specified Benign:6Other:1
Sep 08, 2015
Eurofins Ntd Llc (ga)
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Dec 29, 2017
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BP1, BP4, BP6; This alteration is a missense alteration in a gene for which primarily truncating variants are known to cause disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -

Apr 15, 2016
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 20, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: BRCA2 c.4061C>T (p.Thr1354Met) 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 0.00014 in 243646 control chromosomes (gnomAD and literature). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (0.00014 vs 0.00075), allowing no conclusion about variant significance. The variant, c.4061C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Arver_2001 , Capalbo_2006 , deSanjose_2003 , Laitman_2011) without strong evidence for causality. Cosegregation studies in a family with a history of breast cancer found that this variant did not segregate with disease (Jalkh_2017). Co-occurrences with other pathogenic variants have been reported [BRCA1 c.2071_2071delA, p.Arg691Aspfs (BIC database), CDH1 c.3G>A, p.Met1Ile (Jalkh_2017)], providing supporting evidence for a benign role. Ten other submitters including one expert panel (ENIGMA) have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and classified the variant as benign (n=3) or likely benign (n=7). Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:4
Jun 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BRCA2: BP4 -

Mar 22, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17924331, 12845657, 21520273, 21156238, 21990134, 24055113, 25637381, 24323938, 24728327, 26306726, 11336395, 20104584, 16847550, 20960228, 26689913, 24504028, 27153395, 28202063) -

-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

The BRCA2 p.Thr1354Met variant was identified in 6 of 5256 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast or ovarian cancer (Giannini 2006, Borg 2010, de Sanjosé 2003, Yang 2011). The variant was also identified in the following databases: dbSNP (ID: rs80358656) as ” With other allele”, ClinVar (17 x as benign by ENIGMA, VKGL data share, Invitae, Ambry Genetics, SCRP, as likely benign by EGL Genetics, COGR, Color Genomics, Integrated Genetics, Counsyl, GeneDx and as uncertain significance by BIC), COGR (as likely benign/benign), Cosmic (1x confirmed somatic ovarian carcinoma), LOVD 3.0 (7x as benign or predicted neutral), UMD-LSDB (17 x as likely neutral), BIC Database (12 x as uncertain significance), ARUP Laboratories (as “class 1,not pathogenic or of no clinical significance”). The variant was not identified in MutDB or Zhejiang Colon Cancer Databases. The variant was also identified by our laboratory in 3 individuals with hereditary breast or ovarian cancer and 3 different co-occurring pathogenic variants were identified in each of these individuals (BRCA2, c.7007G>C, p.Arg2336Pro), (BRCA1, c.4096+1G>A, r.spl?) and (BRCA2, c.1103C>A, p.Ser368*), increasing the likelihood that the p.Thr1354Met variant does not have clinical significance. The variant was identified in control databases in 34 of 269620 chromosomes at a frequency of 0.00013 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 23878 chromosomes (freq: 0.00004), Other in 2 of 6330 chromosomes (freq: 0.0003), Latino in 4 of 32684 chromosomes (freq: 0.0001), European Non-Finnish in 22 of 124492 chromosomes (freq: 0.00018), Ashkenazi Jewish in 4 of 9770 chromosomes (freq: 0.0004), and South Asian in 1 of 28178 chromosomes (freq: 0.000035); the variant was not observed in the East Asian or European Finnish populations. The p.Thr1354 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein (Capanu 2011, Easton 2007, Lindor 2012); 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, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Oct 18, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4
May 19, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Mar 10, 2015
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 12, 2017
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 19, 2014
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as 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. -

Hereditary breast ovarian cancer syndrome Benign:2
Aug 04, 2023
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1
Jun 08, 2021
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Breast neoplasm Benign:1
Jun 01, 2014
CSER _CC_NCGL, University of Washington
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.087
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
15
DANN
Benign
0.92
Eigen
Benign
-0.90
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.079
N
M_CAP
Pathogenic
0.35
D
MetaRNN
Benign
0.079
T;T
MetaSVM
Benign
-0.81
T
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-1.9
N;N
REVEL
Benign
0.22
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0040
D;D
Vest4
0.21
MVP
0.72
MPC
0.057
ClinPred
0.039
T
GERP RS
-3.0
gMVP
0.13

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: rs80358656; hg19: chr13-32912553; COSMIC: COSV66447605; API