rs80359249

Variant names:

• chr13-32398418-G-A
• rs80359249
• NM_000059.4:c.9905G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-32398418-G-A
• chr13-32398418-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000059.4(BRCA2):​c.9905G>A​(p.Arg3302Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,614,040 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).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:2
• Conservation: PhyloP100: 6.89

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31381923).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9905G>A	p.Arg3302Lys	missense_variant	Exon 27 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9905G>A	p.Arg3302Lys	missense_variant	Exon 27 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.9536G>A	p.Arg3179Lys	missense_variant	Exon 27 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1963G>A		non_coding_transcript_exon_variant	Exon 26 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*1963G>A		3_prime_UTR_variant	Exon 26 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251204 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135758

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3 Benign:1

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 15, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 24, 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 arginine with lysine at codon 3302 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least four individuals affected with breast cancer and one unaffected individual (PMID: 12491499, 33471991; Leiden Open Variation Database DB-ID BRCA2_002114) and in an individual affected with adenocarcinoma (PMID: 28843361). A multifactorial analysis has reported tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 1.77, 1.1022 and 0.1339, respectively (PMID: 31131967). This variant has been identified in 2/251204 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:3

Apr 21, 2017

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: The BRCA2 c.9905G>A (p.Arg3302Lys) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution and 4/5 in silico tools predict a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing but ESE finder predicts that this variant may introduce an SF2/ASF ESE site at the locus. However, functional studies have shown that the variant has not effect on splicing via RNA analysis from a patient blood sample (Houdayer_2012). This variant was found in the large control database ExAC at a frequency of 0.0000082 (1/121326 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant with differing interpretations, "uncertain significance" and "likely benign." Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available (ie, clinical and functional studies). -

Oct 28, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 08, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in at least one individual with breast cancer (Adem 2003); Also known as BRCA2 10133G>A; This variant is associated with the following publications: (PMID: 12491499, 22505045) -

Hereditary cancer-predisposing syndrome Uncertain:2

Aug 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R3302K variant (also known as c.9905G>A), located in coding exon 26 of the BRCA2 gene, results from a G to A substitution at nucleotide position 9905. The arginine at codon 3302 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Sep 30, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with lysine at codon 3302 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least four individuals affected with breast cancer and one unaffected individual (PMID: 12491499, 33471991; Leiden Open Variation Database DB-ID BRCA2_002114) and in an individual affected with adenocarcinoma (PMID: 28843361). A multifactorial analysis has reported tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 1.77, 1.1022 and 0.1339, respectively (PMID: 31131967). This variant has been identified in 2/251204 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 specified Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related disorder Uncertain:1

Apr 05, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.9905G>A variant is predicted to result in the amino acid substitution p.Arg3302Lys. This variant has been reported in an individual with breast cancer (Table 1, Adem et al. 2003. PubMed ID: 12491499). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32972555-G-A) and is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/52913/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome Benign:1

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-1.2	T
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.87	N;N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.22
MutPred		0.31		Gain of solvent accessibility (P = 0.0059);Gain of solvent accessibility (P = 0.0059);
MVP		0.93
MPC		0.17
ClinPred		0.93	D
GERP RS		5.6
gMVP		0.48

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

LitVar

Other links and lift over

dbSNP: rs80359249; hg19: chr13-32972555;