13-32340168-G-C

Variant names:

• chr13-32340168-G-C
• rs41293499
• NM_000059.4:c.5813G>C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000059.4(BRCA2):​c.5813G>C​(p.Gly1938Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,460,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:5
• Conservation: PhyloP100: -0.0270

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14655748).
• BP6: Variant 13-32340168-G-C is Benign according to our data. Variant chr13-32340168-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 91425.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5813G>C	p.Gly1938Ala	missense_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.5813G>C	p.Gly1938Ala	missense_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.5444G>C	p.Gly1815Ala	missense_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.5813G>C		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 250812 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135672

Gnomad AFR exome AF: 0.0000620

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1460948 Hom.: 0 Cov.: 47 AF XY: 0.0000165 AC XY: 12 AN XY: 726704

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: 0.0000297

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Nov 01, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population, 0.000026 (3/113428 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant was found both in individuals with breast cancer as well as healthy individuals in a large breast cancer association study (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Gly1938Ala variant was not identified in the literature but was identified in dbSNP (ID:rs41293499 ) “With probable-non-pathogenic allele”. The p.Gly1938Ala variant was classified as a likely benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The p.Gly1938 residue is not conserved in mammals and the variant amino acid alanine (Ala) is present in opossum, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) 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 although we would lean towards a more benign role for this variant. This variant is classified as predicted benign. -

Feb 05, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 6041G>C; This variant is associated with the following publications: (PMID: 33850299, 29884841, 32377563, 33939675, 33471991, 31853058) -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Nov 26, 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 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). -

Sep 16, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with alanine at codon 1938 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with a hematological malignancy (PMID: 33850299) and it has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008371). A multifactorial analysis has reported a likelihood ratio for pathogenicity based on personal and family history of 5.281 from log(LR)=0.72270304 for six carriers (PMID: 31853058). This variant has been identified in 4/250812 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:2

Feb 14, 2022

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.5813G>C (p.Gly1938Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250812 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5813G>C has been reported in the literature in individuals affected with Breast cancer (Dorling_2021), Hematological cancer (Singhal_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six Clinvar submitters have assessed the variant since 2014: five classify the variant as of uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Sep 20, 2018

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jul 23, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Likely benign

Review Status: no assertion criteria provided

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 glycine with alanine at codon 1938 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 an individual affected with a hematological malignancy (PMID: 33850299). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008371). This variant has been identified in 4/250812 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. -

Breast and/or ovarian cancer Uncertain:1

Feb 11, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related disorder Uncertain:1

Aug 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.5813G>C variant is predicted to result in the amino acid substitution p.Gly1938Ala. This variant was reported in an individual with a haematological malignancy, an individual with breast cancer, and a healthy control individual (Singhal et al 2021. PubMed ID: 33850299; Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD, and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/91425/). 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 06, 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	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	3.7
DANN	Benign	0.90
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.12	N
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.91	T
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Benign	0.16
Sift	Benign	0.14	T;T
Sift4G	Benign	1.0	T;T
Vest4		0.30
MutPred		0.33		Loss of ubiquitination at K1941 (P = 0.0787);Loss of ubiquitination at K1941 (P = 0.0787);
MVP		0.80
MPC		0.034
ClinPred		0.044	T
GERP RS		1.2
gMVP		0.19

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: rs41293499; hg19: chr13-32914305; COSMIC: COSV99061627;