13-32354990-A-G

Variant names:

• chr13-32354990-A-G
• rs730881593
• NM_000059.4:c.7137A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_000059.4(BRCA2):​c.7137A>G​(p.Gly2379Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,376 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 Likely benign (★★★). Synonymous variant affecting the same amino acid position (i.e. G2379G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:7
• Conservation: PhyloP100: 0.0490
• Publications: 2 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: Benign. The variant received -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 13-32354990-A-G is Benign according to our data. Variant chr13-32354990-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 182294.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=0.049 with no splicing effect.

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.7137A>G	p.Gly2379Gly	synonymous	Exon 14 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.7137A>G	p.Gly2379Gly	synonymous	Exon 14 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.7137A>G	p.Gly2379Gly	synonymous	Exon 14 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.7137A>G	p.Gly2379Gly	synonymous	Exon 14 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.7137A>G	p.Gly2379Gly	synonymous	Exon 14 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.6768A>G	p.Gly2256Gly	synonymous	Exon 14 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461376 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727024

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: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

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

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111622

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

Jul 24, 2014

GeneDx

Significance: 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 criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Jun 19, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:2

Jun 29, 2017

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).

Jun 26, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:2

Nov 12, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting, BP1_Strong c.7137A>G, located in exon 14 of the BRCA2 gene, is predicted to result in no amino acid change, p.(Gly2379=). This position is outside a (potentially) clinically important functional domain and, moreover, the SpliceAI algorithm predicts no significant impact on splicing (BP1_strong). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). To our knowledge, neither relevant clinical data nor well-stablished functional studies have been reported for this variant. This variant has been reported in the ClinVar database (2x benign, 3x likely benign), in the LOVD database (1x benign, 1x likely benign, 3x uncertain significance) and in the BRCA Exchange database as a likely benign variant (‘Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/). Based on currently available information, the variant c.7137A>G should be considered a likely benign variant.

Jul 15, 2015

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.

Hereditary breast ovarian cancer syndrome Benign:1

Jun 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.2
DANN	Benign	0.50
PhyloP100		0.049

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: rs730881593; hg19: chr13-32929127;