NM_000059.4:c.467A>G

Variant names:

• chr13-32326142-A-G
• rs68071147
• NM_000059.4:c.467A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PP3_Moderate BP6

The NM_000059.4(BRCA2):​c.467A>G​(p.Asp156Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000367 in 1,609,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. D156E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:7 O:1
• Conservation: PhyloP100: 1.05
• 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 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 44 uncertain in NM_000059.4
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 13-32326142-A-G is Benign according to our data. Variant chr13-32326142-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 51694.

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.467A>G	p.Asp156Gly	missense	Exon 5 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.467A>G	p.Asp156Gly	missense	Exon 5 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.467A>G	p.Asp156Gly	missense	Exon 5 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.467A>G	p.Asp156Gly	missense	Exon 5 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.467A>G	p.Asp156Gly	missense	Exon 5 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.98A>G	p.Asp33Gly	missense	Exon 5 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000717 AC: 18 AN: 251052 AF XY: 0.0000442

Gnomad AFR exome AF: 0.000557

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000213 AC: 31 AN: 1457012 Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17 AN XY: 725038

African (AFR) AF: 0.000540 AC: 18 AN: 33346

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4934

European-Non Finnish (NFE) AF: 0.00000722 AC: 8 AN: 1108716

Other (OTH) AF: 0.0000498 AC: 3 AN: 60184

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74492

African (AFR) AF: 0.000553 AC: 23 AN: 41584

American (AMR) AF: 0.000131 AC: 2 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68014

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

Alfa AF: 0.0000945 Hom.: 0

Bravo AF: 0.000162

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:5

Apr 20, 2017

Department of Pathology and Molecular Medicine, Queen's University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 27, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.467A>G; p.Asp156Gly variant (rs68071147) is reported in the literature in several individuals affected with breast and/or ovarian cancer (Capanu 2011, Sanz 2010, Suter 2004). This variant is reported in ClinVar (Variation ID: 51694) and is found in the African population with an overall allele frequency of 0.05% (13/24012 alleles) in the Genome Aggregation Database. The aspartate at codon 156 is weakly conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Analyses of splicing (Alamut v.2.11) predict that this variant creates a novel cryptic splice donor site, and mRNA studies indicate that splicing occurs at this cryptic site, resulting in an in-frame deletion of 9 nucleotides at the end of exon 5 (Houdayer 2012, Sanz 2010). However, due to limited information on the clinical impact of the p.Asp156Gly variant, its significance is uncertain at this time. References: Capanu M et al. Assessment of rare BRCA1 and BRCA2 variants of unknown significance using hierarchical modeling. Genet Epidemiol. 2011 Jul;35(5):389-97. Houdayer C et al. Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. Hum Mutat. 2012 Aug;33(8):1228-38. Sanz DJ et al. A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. Clin Cancer Res. 2010 Mar 15;16(6):1957-67. Suter NM et al. BRCA1 and BRCA2 mutations in women from Shanghai China. Cancer Epidemiol Biomarkers Prev. 2004 Feb;13(2):181-9.

Nov 20, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Jul 10, 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.467A>G (p.Asp156Gly) 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. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 5' donor site. These predictions were confirmed by studies demonstrating that the variant results in a 9 nucleotides deletion (r.467_475del) in the majority of the transcripts, which would result in an in-frame deletion of 3 amino acids (p.D156_S158del) at the protein level (Houdayer_2012, Sanz_2010, Fraile-Bethencourt_2019). The variant allele was found at a frequency of 7.2e-05 in 251690 control chromosomes, predominantly at a frequency of 0.00056 within the African or African-American subpopulation in the gnomAD database. This frequency is slightly lower than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer, therefore these data do not allow clear conclusions about the variant. c.467A>G, has been reported in the literature in at least 3 individuals with personal and/or family history of Hereditary Breast and Ovarian Cancer (Suter_2004, Borg_2010, Houdayer_2012), though it was also found in 2 women, older than age 70 years, who have never had cancer (in FLOSSIES database). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. An in vitro study examining the effect of this variant at the protein level using an (intronless) cDNA construct, demonstrated that the Asp156Gly missense variant does not affect the HDR function of BRCA2 in a PARP-inhibitor sensitivity assay (Ikegami_2020). The following publications have been ascertained in the context of this evaluation (PMID: 31825140, 20104584, 21520273, 30883759, 22505045, 32444794, 20215541, 14973102). ClinVar contains an entry for this variant (Variation ID: 51694). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

not provided Uncertain:3 Benign:1 Other:1

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 31, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21520273, 22505045, 20215541, 20104584, 14973102, 23893897, 20167696, 26941049, 16683254, 23348723, 30883759, 31131967, 31825140)

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 05, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.467A>G (p.Asp156Gly) variant has been reported in the published literature in individuals with breast cancer or at high risk for breast and/or ovarian cancer (PMIDs: 14973102 (2004), 20104584 (2010), 26941049 (2016), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)) and prostate cancer (PMID: 36898365 (2023)). Experimental studies suggest that this variant may generate a cryptic splice donor site, resulting in an in-frame deletion of three amino acids (PMIDs: 22505045 (2012), 20215541 (2010), 30233647 (2018), and 30883759 (2019)). An additional functional study determined this variant results in normal function when cells are treated with PARP inhibitors, however, the effect of this variant on the full spectrum of BRCA2 protein function was not investigated (PMID: 32444794 (2020)). The frequency of this variant in the general population, 0.00056 (14/24866 chromosomes in African/African American 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 conflicting predictions that this variant is deleterious or benign. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on BRCA2 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Based on the available information, we are unable to determine the clinical significance of this variant.

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Uncertain significance and reported on 05-05-2022 by Quest Diagnostics Nichols Institute Chantilly. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3

Jul 09, 2007

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 30, 2014

Pathway Genomics

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

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:2

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 25, 2016

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:2

Aug 01, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 18, 2018

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.

Medulloblastoma;C0346153:Familial cancer of breast;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C2931456:Familial prostate cancer;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Benign:1

Jan 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer Benign:1

Feb 27, 2025

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	27
DANN	Uncertain	0.98
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.88	T
PhyloP100		1.0
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.24
Sift	Benign	0.042	D
Sift4G	Benign	0.12	T
Vest4		0.26
MVP		0.86
MPC		0.033
ClinPred		0.018	T
GERP RS		3.7
gMVP		0.14
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs68071147; hg19: chr13-32900279;