rs189026060

Positions:

• chr13-32316609-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000059.4(BRCA2):​c.67+82C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00338 in 1,188,390 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (17 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel U:2 B:5
• Conservation: PhyloP100: -2.73

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 13-32316609-C-G is Benign according to our data. Variant chr13-32316609-C-G is described in ClinVar as [Benign]. Clinvar id is 52164.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32316609-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00347 (3593/1036354) while in subpopulation MID AF= 0.0152 (55/3614). AF 95% confidence interval is 0.012. There are 17 homozygotes in gnomad4_exome. There are 1920 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.67+82C>G		intron_variant		ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.67+82C>G		intron_variant		5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 427 AN: 151918 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000629

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00312

Gnomad FIN AF: 0.000568

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00425

Gnomad OTH AF: 0.00382

GnomAD4 exome AF: 0.00347 AC: 3593 AN: 1036354 Hom.: 17 AF XY: 0.00363 AC XY: 1920 AN XY: 528420

Gnomad4 AFR exome AF: 0.000504

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.00597

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00440

Gnomad4 FIN exome AF: 0.000607

Gnomad4 NFE exome AF: 0.00371

Gnomad4 OTH exome AF: 0.00408

GnomAD4 genome AF: 0.00281 AC: 427 AN: 152036 Hom.: 1 Cov.: 33 AF XY: 0.00258 AC XY: 192 AN XY: 74304

Gnomad4 AFR AF: 0.000627

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00312

Gnomad4 FIN AF: 0.000568

Gnomad4 NFE AF: 0.00425

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00445 Hom.: 1

Bravo AF: 0.00292

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 7.82E-136 -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 17, 2010	- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Vantari Genetics

Feb 04, 2016

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.20
DANN	Benign	0.41

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: rs189026060; hg19: chr13-32890746; COSMIC: COSV104659057; COSMIC: COSV104659057;