13-32340348-A-G

Variant names:

• chr13-32340348-A-G
• rs80358835
• NM_000059.4:c.5993A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_000059.4(BRCA2):​c.5993A>G​(p.Gln1998Arg) 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 1,461,692 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. Q1998H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 1.05
• Publications: 11 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29989013).
• BP6: Variant 13-32340348-A-G is Benign according to our data. Variant chr13-32340348-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 126087.

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.5993A>G	p.Gln1998Arg	missense	Exon 11 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.5993A>G	p.Gln1998Arg	missense	Exon 11 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.5993A>G	p.Gln1998Arg	missense	Exon 11 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.5993A>G	p.Gln1998Arg	missense	Exon 11 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.5993A>G	p.Gln1998Arg	missense	Exon 11 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.5624A>G	p.Gln1875Arg	missense	Exon 11 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250540 AF XY: 0.00

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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461692 Hom.: 0 Cov.: 46 AF XY: 0.00 AC XY: 0 AN XY: 727160

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111922

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Mar 23, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

Apr 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q1998R variant (also known as c.5993A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 5993. The glutamine at codon 1998 is replaced by arginine, an amino acid with highly similar properties. This variant was reported in 0/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

May 04, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 24, 2003

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

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 p.Gln1998Arg variant was not identified in the literature. The variant was identified in dbSNP (ID: rs80358835 ) “With uncertain significance allele”, the ClinVar database 1X (classified as an uncertain significance variant), the BIC database (1X with unknown clinical importance), and UMD (1X as an unknown variant). The identification of this variant in an individual with a co-occuring pathogenic variant (BRCA2: p.Val2969CysfsX7) by our laboratory increased the likelihood the p.Gln1998Arg variant does not have clinical significance. The p.Gln1998 residue is not conserved in mammals and 4 out of 5 computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster, Polyphen-2) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. 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 unknown significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	13
DANN	Uncertain	0.99
Eigen	Benign	0.037
Eigen_PC	Benign	-0.069
FATHMM_MKL	Benign	0.090	N
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.50	T
PhyloP100		1.0
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.40
Sift	Benign	0.036	D
Sift4G	Uncertain	0.028	D
Vest4		0.43
MutPred		0.33		Gain of phosphorylation at S2001 (P = 0.0628)
MVP		0.86
MPC		0.032
ClinPred		0.69	D
GERP RS		4.5
gMVP		0.21
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs80358835; hg19: chr13-32914485; COSMIC: COSV107497831;