13-32340868-G-C

Variant names:

• chr13-32340868-G-C
• rs206076
• NM_000059.4:c.6513G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000059.4(BRCA2):​c.6513G>C​(p.Val2171Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 1,600,494 control chromosomes in the GnomAD database, including 793,827 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. V2171V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.98 (73012 hom., cov: 33)
  • Exomes 𝑓: 1.0 (720815 hom.)
• Consequence: BRCA2 NM_000059.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:30
• Conservation: PhyloP100: -0.864
• Publications: 69 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 13-32340868-G-C is Benign according to our data. Variant chr13-32340868-G-C is described in ClinVar as Benign. ClinVar VariationId is 132780.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

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.6513G>C	p.Val2171Val	synonymous	Exon 11 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.6513G>C	p.Val2171Val	synonymous	Exon 11 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.6513G>C	p.Val2171Val	synonymous	Exon 11 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.6513G>C	p.Val2171Val	synonymous	Exon 11 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.6513G>C	p.Val2171Val	synonymous	Exon 11 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.6144G>C	p.Val2048Val	synonymous	Exon 11 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.979 AC: 148951 AN: 152216 Hom.: 72963 Cov.: 33

Gnomad AFR AF: 0.926

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.992

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.975

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.985

GnomAD2 exomes AF: 0.994 AC: 238206 AN: 239596 AF XY: 0.996

Gnomad AFR exome AF: 0.925

Gnomad AMR exome AF: 0.996

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.996

GnomAD4 exome AF: 0.998 AC: 1444784 AN: 1448160 Hom.: 720815 Cov.: 51 AF XY: 0.998 AC XY: 718213 AN XY: 719734

African (AFR) AF: 0.921 AC: 29866 AN: 32444

American (AMR) AF: 0.995 AC: 41041 AN: 41238

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 25529 AN: 25530

East Asian (EAS) AF: 1.00 AC: 39572 AN: 39572

South Asian (SAS) AF: 1.00 AC: 82620 AN: 82642

European-Finnish (FIN) AF: 1.00 AC: 53152 AN: 53152

Middle Eastern (MID) AF: 0.992 AC: 5631 AN: 5674

European-Non Finnish (NFE) AF: 1.00 AC: 1107919 AN: 1108152

Other (OTH) AF: 0.995 AC: 59454 AN: 59756

GnomAD4 genome AF: 0.978 AC: 149058 AN: 152334 Hom.: 73012 Cov.: 33 AF XY: 0.979 AC XY: 72946 AN XY: 74494

African (AFR) AF: 0.926 AC: 38462 AN: 41558

American (AMR) AF: 0.992 AC: 15189 AN: 15304

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3470 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5185 AN: 5186

South Asian (SAS) AF: 0.999 AC: 4827 AN: 4830

European-Finnish (FIN) AF: 1.00 AC: 10630 AN: 10630

Middle Eastern (MID) AF: 0.973 AC: 286 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68013 AN: 68034

Other (OTH) AF: 0.985 AC: 2084 AN: 2116

Alfa AF: 0.923 Hom.: 15838

Bravo AF: 0.976

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	8	Breast-ovarian cancer, familial, susceptibility to, 2 (8)
-	-	4	Hereditary breast ovarian cancer syndrome (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	1	Familial cancer of breast (1)
-	-	1	Fanconi anemia complementation group D1 (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.10
DANN	Benign	0.59
PhyloP100		-0.86
Mutation Taster		=100/0	polymorphism (auto)

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: rs206076; hg19: chr13-32915005; COSMIC: COSV66458663;