13-32326554-A-G

Variant names:

• chr13-32326554-A-G
• rs397507798
• NM_000059.4:c.572A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_000059.4(BRCA2):​c.572A>G​(p.Asp191Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D191A?) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 6.27

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_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32326553-GA-GCT is described in Lovd as [Pathogenic].
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 13-32326554-A-G is Pathogenic according to our data. Variant chr13-32326554-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51920.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.572A>G	p.Asp191Gly	missense_variant	Exon 7 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.572A>G	p.Asp191Gly	missense_variant	Exon 7 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.203A>G	p.Asp68Gly	missense_variant	Exon 7 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.572A>G		non_coding_transcript_exon_variant	Exon 6 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461736 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727166

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:1

Oct 14, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp191Gly variant in BRCA2 has been reported in 2 individuals with early-onset breast cancer (Gaildrat 2012). It was absent from large population studies. Computational prediction tools and conservation analysis suggest that the p.Asp191Gly variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additionally, in vitro splicing assays provide evidence that this variant leads to a splicing change, resulting in the in-frame deletion of 20 amino acids (Gaildrat 2012, Fraile-Bethencourt 2019); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). ACMG/AMP Criteria applied: PM2, PS3_Moderate, PP3, PS4_Supporting. -

Hereditary cancer-predisposing syndrome Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.572A>G variant (also known as p.D191G), located in coding exon 6 of the BRCA2 gene, results from an A to G substitution at nucleotide position 572. RNA studies have demonstrated that this alteration results in abnormal splicing that results in the in-frame loss of 20 amino acids (Ambry internal data; Gaildrat P et al. J Med Genet, 2012 Oct;49:609-17; Fraile-Bethencourt E et al. J Pathol, 2019 Aug;248:409-420); however, the exact functional impact of the deleted amino acids is unknown at this time. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Based on the available evidence, the clinical significance of this variant remains unclear. -

Familial cancer of breast Other:1

-

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.010	D;D
Vest4		0.59
MutPred		0.14		Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);
MVP		0.93
MPC		0.18
ClinPred		0.98	D
GERP RS		5.5
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.87		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397507798; hg19: chr13-32900691;