rs55775473

Positions:

• chr13-32397030-G-A
• chr13-32397030-G-C
• chr13-32397030-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000059.4(BRCA2):​c.9634G>A​(p.Gly3212Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. 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 Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in Lovd.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.13

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21687385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9634G>A	p.Gly3212Arg	missense_variant	26/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9634G>A	p.Gly3212Arg	missense_variant	26/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.9265G>A	p.Gly3089Arg	missense_variant	26/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1692G>A		non_coding_transcript_exon_variant	25/26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*1692G>A		3_prime_UTR_variant	25/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251338 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135844

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461736 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727186

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: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 25, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 16, 2016	Variant summary: The BRCA2 c.9634G>A (p.Gly3212Arg) variant causes a missense change involving a conserved nucleotide with 3/5 in silico tools predicting a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was not found in controls (ExAC, 1000 Gs, or ESP). However, it should be noted another variant, c.9634G>C (scored NV) causing the same missense change was observed in the large, broad control population, ExAC, with an allele frequency of 62/121384, along with being reported in one database to co-occur with multiple deleterious BRCA2 variants and multiple clinical laboratories via ClinVar citing the variant as "benign/likely benign." The variant of interest, to our knowledge, has not been reported in reputable databases/clinical laboratories. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a "VUS-possibly benign." -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.97
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.29	N
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.95	T
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.15
Sift	Benign	0.071	T;T
Sift4G	Uncertain	0.0080	D;D
Vest4		0.34
MutPred		0.33		Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);
MVP		0.84
MPC		0.064
ClinPred		0.35	T
GERP RS		3.0
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: rs55775473; hg19: chr13-32971167;