13-32355184-A-T

Variant names:

• chr13-32355184-A-T
• rs431825352
• NM_000059.4:c.7331A>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000059.4(BRCA2):​c.7331A>T​(p.Asp2444Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,613,820 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. D2444G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:5
• Conservation: PhyloP100: -1.50
• Publications: 6 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027618498).
• BP6: Variant 13-32355184-A-T is Benign according to our data. Variant chr13-32355184-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 140873.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.7331A>T	p.Asp2444Val	missense	Exon 14 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.7331A>T	p.Asp2444Val	missense	Exon 14 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.7331A>T	p.Asp2444Val	missense	Exon 14 of 27	NP_001393649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.7331A>T	p.Asp2444Val	missense	Exon 14 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.7331A>T	p.Asp2444Val	missense	Exon 14 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.6962A>T	p.Asp2321Val	missense	Exon 14 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152210 Hom.: 1 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: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000877 AC: 22 AN: 250804 AF XY: 0.0000959

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1461492 Hom.: 0 Cov.: 35 AF XY: 0.0000523 AC XY: 38 AN XY: 727054

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.000661 AC: 57 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111738

Other (OTH) AF: 0.0000828 AC: 5 AN: 60378

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152328 Hom.: 1 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74486

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.000124 AC: 15

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Feb 09, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 14, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with history of breast and/or ovarian cancer (PMID: 29470806); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as 7559A>T; This variant is associated with the following publications: (PMID: 31422574, 32377563, 29884841, 31853058, 29470806)

Jan 02, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.7331A>T (p.Asp2444Val) variant has been reported in the published literature in a cohort of individuals with breast and/or ovarian cancer (PMID: 29470806 (2018), 32885271 (2021)). This variant has also been identified in a reportedly healthy individual (PMID: 31422574 (2019)). The frequency of this variant in the general population, 0.00072 (22/30460 chromosomes in South Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Aug 04, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Jul 28, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 29, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

not specified Uncertain:1 Benign:1

May 13, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.7331A>T; p.Asp2444Val variant (rs431825352) is reported in the literature in at least one individual in a breast and/or ovarian cancer cohort (Singh 2018). This variant is reported as a variant of uncertain significance by multiple laboratories in ClinVar (Variation ID: 140873), and is found in the South Asian population with an allele frequency of 0.072% (22/30460 alleles) in the Genome Aggregation Database. The aspartic acid at codon 2444 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Asp2444Val variant is uncertain at this time. References: Singh J et al. Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations. Breast Cancer Res Treat. 2018 Jul;170(1):189-196.

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.Asp2444Val variant was not identified in the literature nor was it identified in the MutDB, LOVD 3.0, UMD-LSDB, BIC, ARUP Laboratories, Cosmic, and Zhejiang Colon Cancer databases. The variant was identified in dbSNP (ID: rs431825352) as “Uncertain Significance allele” and in the ClinVar and Clinvitae databases as uncertain significance by Ambry Genetics and Invitae. The variant was also identified in control databases in 22 of 245620 chromosomes at a frequency of 0.00009 in the following populations: South Asian in 21 of 30616 chromosomes (freq. 0.0007) and Other in 1 of 5476 chromosomes (freq. 0.0002), but was not seen in African, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, and European Finnish populations increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017)". The p.Asp2444 residue is not conserved in mammals and the variant amino acid (Val) is present in Rattus norvegicus, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; increasing the likelihood that this variant does not have clinical significance: however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Breast cancer type 2 susceptibility protein functional domains increasing the likelihood that it may have clinical significance. 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.

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

Nov 28, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome Benign:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.085
DANN	Benign	0.56
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.041	N
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.91	T
PhyloP100		-1.5
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.25
Sift	Benign	0.14	T
Sift4G	Benign	0.23	T
Vest4		0.24
MutPred		0.10		Gain of methylation at K2446 (P = 0.0918)
MVP		0.65
MPC		0.025
ClinPred		0.013	T
GERP RS		-0.76
gMVP		0.38
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs431825352; hg19: chr13-32929321;