13-32354863-C-T

Position:

chr13-32354863-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000059.4(BRCA2):c.7010C>T(p.Thr2337Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000638 in 1,567,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12B:3

Conservation

PhyloP100: 0.962

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]

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30671978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.7010C>T	p.Thr2337Ile	missense_variant, splice_region_variant	14/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.7010C>T	p.Thr2337Ile	missense_variant, splice_region_variant	14/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152168

Hom.:

Cov.:

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250362

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135720

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000671

AC:

AN:

1415760

Hom.:

Cov.:

AF XY:

0.0000693

AC XY:

AN XY:

707000

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000888

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:3Benign:1

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	This missense variant replaces threonine with isoleucine at codon 2337 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 detected in individuals with personal and/or family history of breast and/or ovarian cancer (PMID: 15800311, 16683254, 27376475) and in a breast cancer case-control meta-analysis in 5/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001509). This variant also has been detected in unaffected individuals (PMID: 24448499; FLOSSIES database). A multifactorial analysis has reported co-occurrence and family history likelihood ratios for pathogenicity of 1.1293 and 0.5103, respectively (PMID: 31131967). This variant has been identified in 7/281770 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 13, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -

not provided

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 11, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 7238C>T; Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Gomez-Garcia 2005, van der Hout 2006); This variant is associated with the following publications: (PMID: 31131967, 16683254, 15800311, 27376475) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2024	This missense variant replaces threonine with isoleucine at codon 2337 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). A functional study has shown that this variant does not impact cell viability or drug sensitivity in Brca2-deficient mouse embryonic stem cells (PMID: 37922907). This variant has been detected in individuals with personal and/or family history of breast and/or ovarian cancer (PMID: 15800311, 16683254, 27376475, 32885271) and in a breast cancer case-control meta-analysis in 5/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001509). This variant also has been detected in unaffected individuals (PMID: 24448499; FLOSSIES database). A multifactorial analysis has reported co-occurrence and family history likelihood ratios for pathogenicity of 1.1293 and 0.5103, respectively (PMID: 31131967). This variant has been identified in 7/281770 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 29, 2022	The p.T2337I variant (also known as c.7010C>T), located in coding exon 13 of the BRCA2 gene, results from a C to T substitution at nucleotide position 7010. The threonine at codon 2337 is replaced by isoleucine, an amino acid with similar properties. This variant has been reported in multiple individuals and/or families who met eligibility criteria for hereditary breast and/or ovarian cancer syndrome (Gómez-García EB et al. J Clin Oncol, 2005 Apr;23:2185-90; van der Hout AH et al. Hum Mutat, 2006 Jul;27:654-66; Schenkel LC et al. J Mol Diagn, 2016 09;18:657-667; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is not 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 22, 2021

Variant summary: BRCA2 c.7010C>T (p.Thr2337Ile) 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. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 250362 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7010C>T has been reported in the literature in a family undergoing complete BRCA 1 and 2 mutational analyses, a patient with Ovarian Cancer and in a family of Breast and/or Ovarian cancer (GomezGarcia_2005, Kanchi_2014, vanderHout_2006). Co-occurrence with anther pathogenic variant has been reported (BRCA1 c.2331T>A, p.Tyr777Ter), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Chordoma

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Integrative Tumor Epidemiology Branch, National Institutes of Health

Mar 22, 2021

No impact on ES cell survival or drug sensitivity (no impact on BRCA2 function) -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The BRCA2 p.Thr2337Ile variant was identified in 2 of 1666 proband chromosomes (frequency: 0.001) from Dutch and Canadian individuals or families with breast or ovarian cancer (van der Hout 2006, Schenkel 2016). The variant was identified in dbSNP (ID: rs80358927) as â€šÃ„ÃºWith other alleleâ€šÃ„Ã¹, ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and 3 other submitters; and as likely benign by Diagnostic Laboratory University Medical Center Groningen), and LOVD 3.0. The variant was not identified in UMD-LSDB. The variant was identified in control databases in 6 of 277036 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017), and was observed in the following populations: Other in 1 of 6458 chromosomes (freq: 0.0002) and European Non-Finnish in 5 of 126590 chromosomes (freq: 0.00004); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Thr2337 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Ile impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The p.Thr2337Ile variant occurs in third base of the exon, outside of the splicing consensus sequence, and computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a significant difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 27, 2024

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2337 of the BRCA2 protein (p.Thr2337Ile). This variant is present in population databases (rs80358927, gnomAD 0.004%). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer and in individuals in the Breast Cancer Information Core database. However, in one of these individuals a pathogenic variant was also identified in BRCA1, which suggests that this c.7010C>T BRCA2 variant was not the primary cause of disease (PMID: 10923033, 15800311, 16683254, 27376475). ClinVar contains an entry for this variant (Variation ID: 52248). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 35762214). 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

0.12

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.18

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.31

T;T

MetaSVM

Benign

-0.74

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.4

N;N

REVEL

Uncertain

0.45

Sift

Benign

0.094

T;T

Sift4G

Benign

0.27

T;T

Vest4

0.36

MVP

0.91

MPC

0.030

ClinPred

0.15

GERP RS

3.9

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over