13-32340794-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000059.4(BRCA2):c.6439C>T(p.His2147Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,906 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. H2147R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: -0.0770

Publications

6 publications found

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 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

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21589041).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.6439C>T	p.His2147Tyr	missense_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
BRCA2	ENST00000380152.8 link	c.6439C>T	p.His2147Tyr	missense_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7 link	c.6070C>T	p.His2024Tyr	missense_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2 link	n.6439C>T		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441906

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716776

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31990

American (AMR)

AF:

0.00

AC:

AN:

39176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25006

East Asian (EAS)

AF:

0.00

AC:

AN:

39540

South Asian (SAS)

AF:

0.00

AC:

AN:

82030

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52910

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5642

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106202

Other (OTH)

AF:

0.00

AC:

AN:

59410

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3Benign:1

Sep 20, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces histidine with tyrosine at codon 2147 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has not been identified 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 30, 2017

True Health Diagnostics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 22, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.H2147Y variant (also known as c.6439C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 6439. The histidine at codon 2147 is replaced by tyrosine, an amino acid with similar properties. 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. -

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). -

BRCA2-related cancer predisposition

Uncertain:1

Jun 11, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

Nov 22, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Also known as 6667C>T; This variant is associated with the following publications: (PMID: 27150160) -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Jul 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. 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. ClinVar contains an entry for this variant (Variation ID: 141075). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 2147 of the BRCA2 protein (p.His2147Tyr). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Benign

-0.17

CADD

Benign

1.7

(source)

DANN

Benign

0.93

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.057

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-0.80

PhyloP100

-0.077

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.0

N;N

REVEL

Uncertain

0.51

Sift

Uncertain

0.013

D;D

Sift4G

Benign

0.072

T;T

Vest4

0.39

MutPred

0.26

Loss of methylation at K2150 (P = 0.0654);Loss of methylation at K2150 (P = 0.0654);

MVP

0.88

MPC

0.041

ClinPred

0.078

GERP RS

2.1

gMVP

0.30

Mutation Taster

=83/17

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over