13-32354863-C-T

Variant names:

• chr13-32354863-C-T
• rs80358927
• NM_000059.4:c.7010C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2337A) has been classified 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:12 B:3
• Conservation: PhyloP100: 0.962
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 39 uncertain in NM_000059.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.30671978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7010C>T	p.Thr2337Ile	missense_variant, splice_region_variant	Exon 14 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7010C>T	p.Thr2337Ile	missense_variant, splice_region_variant	Exon 14 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.6641C>T	p.Thr2214Ile	missense_variant, splice_region_variant	Exon 14 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7010C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 13 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152168 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 250362 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000671 AC: 95 AN: 1415760 Hom.: 0 Cov.: 28 AF XY: 0.0000693 AC XY: 49 AN XY: 707000

African (AFR) AF: 0.00 AC: 0 AN: 32404

American (AMR) AF: 0.00 AC: 0 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25858

East Asian (EAS) AF: 0.00 AC: 0 AN: 39432

South Asian (SAS) AF: 0.00 AC: 0 AN: 85266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.0000888 AC: 95 AN: 1070184

Other (OTH) AF: 0.00 AC: 0 AN: 58864

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000276 Hom.: 0

Bravo AF: 0.0000302

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2 Benign:2

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 11, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2 Benign:1

Dec 13, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:2

Feb 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 02, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Uncertain:1

Feb 25, 2025

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.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. Consensus agreement among computation 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. 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). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.2331T>A, p.Tyr777Ter). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15800311, 16683254, 24448499). ClinVar contains an entry for this variant (Variation ID: 52248). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Chordoma Uncertain:1

Mar 22, 2021

Integrative Tumor Epidemiology Branch, National Institutes of Health

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

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

BRCA2-related cancer predisposition Uncertain:1

May 14, 2024

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 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. -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 “With other allele”, 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

Feb 27, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Dec 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". 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, 37922907). 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	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	16
DANN	Uncertain	1.0
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.18	N
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.74	T
PhyloP100		0.96
PrimateAI	Benign	0.33	T
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	T
GERP RS		3.9
gMVP		0.30
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs80358927; hg19: chr13-32929000;