chr13-32379351-A-G

Variant names:

• chr13-32379351-A-G
• rs397508008
• NM_000059.4:c.8789A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000059.4(BRCA2):​c.8789A>G​(p.Asn2930Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,570 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. N2930T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.42
• Publications: 5 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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13674605).
• BP6: Variant 13-32379351-A-G is Benign according to our data. Variant chr13-32379351-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 52679.

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.8789A>G	p.Asn2930Ser	missense	Exon 22 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.8789A>G	p.Asn2930Ser	missense	Exon 22 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.8789A>G	p.Asn2930Ser	missense	Exon 22 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.8789A>G	p.Asn2930Ser	missense	Exon 22 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.8789A>G	p.Asn2930Ser	missense	Exon 22 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.8420A>G	p.Asn2807Ser	missense	Exon 22 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461570 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727076

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

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111852

Other (OTH) AF: 0.00 AC: 0 AN: 60374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

BRCA2-related disorder Uncertain:1

Aug 25, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.8789A>G variant is predicted to result in the amino acid substitution p.Asn2930Ser. This variant has been reported in an individual with breast cancer (Table 2, Hansen et al. 2011. PubMed ID: 21318380). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as uncertain significnace in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/52679/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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.Asn2930Ser variant was identified in 1 of 1331 proband chromosomes (frequency: 0.0001) from individuals or families from East Denmark with Ovarian and Breast cancers and was not identified in 198 control chromosomes from healthy individuals (Hansen 2011). The variant is listed in the dbSNP database (rs397508008) but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined. The p.Asn2930Ser variant was also identified in Clinvar database from one submitter, Invitae, who provided no classification The p.Asn2930Ser variant was not identified in NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014), Fanconi Anaemia LOVD, COSMIC, Clinvitae, GeneInsight VariantWire through the Canadian Open Genetics Repository (http://opengenetics.ca/), BIC, ARUP Laboratories, MutDB or BRCA Share UMD databases. The p.Asn2930 residue is conserved in mammals and lower organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. It was noted that the PolyPhen prediction is inconsistent given the strong conservation in mammals and lower organisms; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% chance that the variant creates a cryptic 3’ acceptor site; this is not very predictive of pathogenicity. Additionally, the variant was classified as a VUS in the East Denmark study, but in silico analysis (AGVGD) suggested the variant might be pathogenic (Hansen 2011). 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.

Hereditary breast ovarian cancer syndrome Uncertain:1

Jun 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 2930 of the BRCA2 protein (p.Asn2930Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 21318380). ClinVar contains an entry for this variant (Variation ID: 52679). 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.

Hereditary cancer-predisposing syndrome Benign:1

May 22, 2025

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Uncertain	1.0
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.90	T
PhyloP100		2.4
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.12
Sift	Benign	0.12	T
Sift4G	Benign	0.16	T
Vest4		0.21
MutPred		0.21		Gain of phosphorylation at N2930 (P = 0.0373)
MVP		0.79
MPC		0.073
ClinPred		0.36	T
GERP RS		0.59
gMVP		0.11
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397508008; hg19: chr13-32953488;