chr13-32340015-C-T

Position:

chr13-32340015-C-T

Variant summary

Our verdict is Likely benign. Variant got -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. 12/19 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: not found (cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:1

Conservation

PhyloP100: -0.863

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:

BRCA2 (HGNC:):

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.5660C>T	p.Thr1887Met	missense_variant	11/27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.5660C>T	p.Thr1887Met	missense_variant	11/27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 linkuse as main transcript	c.5291C>T	p.Thr1764Met	missense_variant	11/27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 linkuse as main transcript	n.5660C>T		non_coding_transcript_exon_variant	10/26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000240

AC:

AN:

249646

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135010

show subpopulations

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 SAS exome

AF:

0.0000332

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1460516

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726458

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000674

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000350

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 04, 2023	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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 02, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 16, 2022	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. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 01, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 10, 2016	- -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jun 19, 2014	- -

BRCA2-related cancer predisposition

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 22, 2024

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

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 13, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 20, 2023

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) -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 01, 2023

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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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

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

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-0.92

PrimateAI

Benign

0.24

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

GERP RS

0.39

gMVP

0.25

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.

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