13-32325142-A-G

Variant names:

• chr13-32325142-A-G
• rs80358627
• NM_000059.4:c.383A>G

Variant summary

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

The NM_000059.4(BRCA2):​c.383A>G​(p.Asp128Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,608,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. D128V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:3
• Conservation: PhyloP100: 0.181
• Publications: 10 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 0 ACMG points.

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.383A>G	p.Asp128Gly	missense	Exon 4 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.383A>G	p.Asp128Gly	missense	Exon 4 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.383A>G	p.Asp128Gly	missense	Exon 4 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.383A>G	p.Asp128Gly	missense	Exon 4 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.383A>G	p.Asp128Gly	missense	Exon 4 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.14A>G	p.Asp5Gly	missense	Exon 4 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251152 AF XY: 0.00000736

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1456266 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 724848

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53234

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

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1107108

Other (OTH) AF: 0.00 AC: 0 AN: 60210

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74330

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000267 Hom.: 0

Bravo AF: 0.0000151

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:4

Apr 16, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 15, 1999

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 13, 2023

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 aspartic acid with glycine at codon 128 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). A minigene splicing assay has reported a partial splicing defect for this variant (PMID: 30883759). To our knowledge, protein functional studies have not been performed for this variant. This variant has been reported in one individual each affected with breast cancer and colorectal cancer and in two individuals affected with prostate cancer (PMID: 10690392, 24814045, 31214711, 33471991; Leiden Open Variation Database DB-ID BRCA2_006255). This variant also has been reported in at least three individuals unaffected with cancer in breast and pancreatic cancer case-control studies (PMID: 30287823, 32980694, 33471991; Leiden Open Variation Database DB-ID BRCA2_006255). This variant has been identified in 1/251152 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.

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:2

Oct 23, 2024

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.

Mar 16, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Feb 19, 2025

Catlab - Consorci Sanitari de Terrassa

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on currently available information, this variant should be considered as Likely Benign according to ClinGen-BRCA2 v1.2.0 guidelines. PP3, BP7_strong(RNA); point system classification.

Nov 16, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with glycine at codon 128 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). A minigene splicing assay has reported a partial splicing defect for this variant (PMID: 30883759). To our knowledge, protein functional studies have not been performed for this variant. This variant has been reported in one individual each affected with breast cancer and colorectal cancer and in two individuals affected with prostate cancer (PMID: 10690392, 24814045, 31214711, 33471991; Leiden Open Variation Database DB-ID BRCA2_006255). This variant also has been reported in at least three individuals unaffected with cancer in breast and pancreatic cancer case-control studies (PMID: 30287823, 32980694, 33471991; Leiden Open Variation Database DB-ID BRCA2_006255). This variant has been identified in 1/251152 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 provided Uncertain:2

Aug 20, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Also known as BRCA2 611A>G; This variant is associated with the following publications: (PMID: 30287823, 24814045, 10690392, 30883759)

Apr 12, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Jul 09, 2024

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Kriterien überprüfen nach ENIGMA Entscheidungsbaum; According to the ClinGen ENIGMA BRCA2 v1.1.0 criteria we chose these criteria: PP3 (supporting pathogenic): SpliceAI: BRCA2: 0.39 , BP7 (strong benign): BP7_STR(RNA); Fraile Bethencourt 2019 Minigene Exons 2–9: Full-Length Transcript 78%; Appendices Guidelines Tbl.9: Cutoff Referenztranskript 30%

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 128 of the BRCA2 protein (p.Asp128Gly). This variant is present in population databases (rs80358627, gnomAD 0.0009%). This missense change has been observed in individual(s) with personal or family history of colorectal cancer, breast cancer, and/or prostate cancer (PMID: 10690392, 24814045, 31214711, 33606809, 34413315, 35264596). ClinVar contains an entry for this variant (Variation ID: 51538). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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.

not specified Uncertain:1

Jun 26, 2025

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.383A>G (p.Asp128Gly) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 1e-05 in 298614 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.383A>G has been observed in settings of multi-gene panel testing in individuals affected with breast cancer or personal and/or family history of cancer, often reported as a VUS (e.g. Li_2020, Sandoval_2021, Herzog_2021, Guindalini_2022, deOliveira_2022, Gifoni_2022), in colorectal cancer (Garre_2014), or male breast cancer (e.g. Diez_2002), in all cases without evidence of causality. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. 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: 10690392, 30883759, 24814045, 35957908, 35264596, 34413315, 31853058, 30287823, 33606809, 35534704). ClinVar contains an entry for this variant (Variation ID: 51538). Based on the evidence outlined above, the variant was classified as uncertain significance.

Familial cancer of breast Uncertain:1

Feb 08, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.93
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.026	N
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-0.92	T
PhyloP100		0.18
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.25
Sift	Benign	0.11	T
Sift4G	Benign	0.091	T
Vest4		0.20
MutPred		0.14		Loss of stability (P = 0.0176)
MVP		0.65
MPC		0.022
ClinPred		0.029	T
GERP RS		-1.6
gMVP		0.23
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: -1

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

Other links and lift over

dbSNP: rs80358627; hg19: chr13-32899279;