13-32340015-C-T

Variant names:

• chr13-32340015-C-T
• rs397507795
• NM_000059.4:c.5660C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000059.4(BRCA2):​c.5660C>T​(p.Thr1887Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,460,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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. T1887R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:1
• Conservation: PhyloP100: -0.863
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20583016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5660C>T	p.Thr1887Met	missense_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.5660C>T	p.Thr1887Met	missense_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.5291C>T	p.Thr1764Met	missense_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.5660C>T		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000240 AC: 6 AN: 249646 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1460516 Hom.: 0 Cov.: 46 AF XY: 0.0000151 AC XY: 11 AN XY: 726458

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.0000674 AC: 3 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39664

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111626

Other (OTH) AF: 0.0000166 AC: 1 AN: 60352

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000267 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3 Benign:1

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). -

Feb 02, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 31, 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 methionine at codon 1887 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least three suspected hereditary breast and ovarian cancer families (PMID: 15172753, 28351343, 29470806), over ten individuals affected with breast cancer (PMID: 30287823, 33471991, 35373174; Color internal data), and three individuals each affected with prostate and colorectal cancer (PMID: 31214711, 33309985). This variant also has been reported in at least eight unaffected individuals from breast, pancreatic, prostate and colorectal cancer case-control studies (PMID: 31214711, 32980694, 33309985, 33471991). This variant has been identified in 6/249646 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. -

Aug 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T1887M variant (also known as c.5660C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 5660. The threonine at codon 1887 is replaced by methionine, an amino acid with similar properties. This variant has been reported in breast and/or ovarian cancer patients in cohorts from Cyprus, Iran, India and Japan, in addition to controls from Japan (Hadjisavvas A et al. Cancer Genet Cytogenet. 2004 Jun;151(2):152-6); Tabarestani S et al. Int J Ca Manage. 2017 Dec;e60392; Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196; Momozawa Y et al. Nat Commun, 2018 10;9:4083). In one study, this variant was reported in 7/60,466 breast cancer cases and in 4/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439). 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. -

not specified Uncertain:2

Feb 01, 2024

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.5660C>T (p.Thr1887Met) results in a non-conservative amino acid change located in the outside of any known domain or repeat of the encoded protein sequence. Four 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 249746 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5660C>T has been reported in the literature in individuals affected with breast cancer as well as unaffected controls (example, Hadjisavvas_2004, Tabarestani_2018, Kim_2017, Neveling_2017, Loizidou_2017, Momozawa_2018, Dorling_2021, Okawa_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA1 c.3640G>T , p.Glu1214X), providing supporting evidence for a benign role. 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: 25348012, 33471991, 15172753, 28351343, 27882536, 30287823, 27974384, 36243179, 22895193,Tabarestani_2018). ClinVar contains an entry for this variant (Variation ID: 51901).Based on the evidence outlined above, the variant was classified as uncertain significance. -

Oct 10, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jun 19, 2014

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 02, 2020

BRCAlab, Lund University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

BRCA2-related cancer predisposition Uncertain:1

Feb 22, 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 methionine at codon 1887 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 at least three suspected hereditary breast and ovarian cancer families (PMID: 15172753, 28351343, 29470806), over ten individuals affected with breast cancer (PMID: 30287823, 33471991, 35373174; Color internal data), and three individuals each affected with prostate and colorectal cancer (PMID: 31214711, 33309985). This variant also has been reported in at least eight unaffected individuals from breast, pancreatic, prostate and colorectal cancer case-control studies (PMID: 31214711, 32980694, 33309985, 33471991). This variant has been identified in 6/249646 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. -

BRCA2-related disorder Uncertain:1

Nov 13, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.5660C>T variant is predicted to result in the amino acid substitution p.Thr1887Met. This variant has been reported in an individuals with a personal and/or family history of breast and/or ovarian cancer (Table 2, Hadjisavvas et al. 2004. PubMed ID: 15172753; Table S2, Loizidou et al. 2016. PubMed ID: 27882536; Singh et al. 2018. PubMed ID: 29470806; Sup. Data 1, Momozawa et al. 2018. PubMed ID: 30287823; Table S2, Okawa et al. 2022. PubMed ID: 36243179). It has been reported in individuals with biliary tract cancer (Table S2, Okawa et al. 2022. PubMed ID: 36243179). It has also been reported in a control individual from a breast cancer cohort study and a control individual from a biliary tract cancer cohort study (Sup. Data 2, Momozawa et al. 2018. PubMed ID: 30287823; Table S2, Okawa et al. 2022. PubMed ID: 36243179). This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32914152-C-T?dataset=gnomad_r2_1). This variant occurs within a region of the BRCA2 gene that is predicted to be tolerant to missense variation (Table 2, Dines et al. 2020. PubMed ID: 31911673). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Mar 20, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Present in individuals with breast and/or ovarian cancer, but also identified in unaffected controls (Hadjisavvas et al., 2004; Singh et al., 2018; Momozawa et al., 2018; Dorling et al., 2021; Kim et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5888C>T; This variant is associated with the following publications: (PMID: 15172753, Tabarestani2017[article], 32377563, 25348012, 22895193, 29884841, 28351343, 30287823, 27974384, 35373174, 33471991, 27882536, 29470806, 31871109) -

Familial cancer of breast;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1

Dec 11, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Jan 28, 2025

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 methionine, which is neutral and non-polar, at codon 1887 of the BRCA2 protein (p.Thr1887Met). This variant is present in population databases (rs397507795, gnomAD 0.01%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 15172753, 28351343, 29470806, 30287823). ClinVar contains an entry for this variant (Variation ID: 51901). 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	0.096
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	0.93
DANN	Benign	0.58
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.046	N
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.92	T
PhyloP100		-0.86
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.31
Sift	Benign	0.25	T;T
Sift4G	Benign	0.17	T;T
Vest4		0.31
MutPred		0.34		Loss of methylation at K1888 (P = 0.0263);Loss of methylation at K1888 (P = 0.0263);
MVP		0.86
MPC		0.031
ClinPred		0.35	T
GERP RS		0.39
gMVP		0.25
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs397507795; hg19: chr13-32914152; COSMIC: COSV66452702;