rs1799955

Variant names:

• chr13-32355095-A-G
• rs1799955
• NM_000059.4:c.7242A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-32355095-A-G
• chr13-32355095-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000059.4(BRCA2):​c.7242A>G​(p.Ser2414Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 1,613,446 control chromosomes in the GnomAD database, including 41,275 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. S2414S) has been classified as Likely benign. The gene BRCA2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.22 (3839 hom., cov: 32)
  • Exomes 𝑓: 0.22 (37436 hom.)
• Consequence: BRCA2 NM_000059.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:31
• Conservation: PhyloP100: 0.0960
• Publications: 105 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):

• BRCA2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• 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

Specifications for BRCA2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 13-32355095-A-G is Benign according to our data. Variant chr13-32355095-A-G is described in ClinVar as Benign. ClinVar VariationId is 126133.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=0.096 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.381 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.7242A>G	p.Ser2414Ser	synonymous	Exon 14 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.7242A>G	p.Ser2414Ser	synonymous	Exon 14 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.7242A>G	p.Ser2414Ser	synonymous	Exon 14 of 27	NP_001393649.1	A0A8V8TPZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.7242A>G	p.Ser2414Ser	synonymous	Exon 14 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.7242A>G	p.Ser2414Ser	synonymous	Exon 14 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.6873A>G	p.Ser2291Ser	synonymous	Exon 14 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33669 AN: 152022 Hom.: 3840 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.396

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.227

GnomAD2 exomes AF: 0.225 AC: 56617 AN: 251236 AF XY: 0.225

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.180

Gnomad ASJ exome AF: 0.208

Gnomad EAS exome AF: 0.382

Gnomad FIN exome AF: 0.237

Gnomad NFE exome AF: 0.216

Gnomad OTH exome AF: 0.223

GnomAD4 exome AF: 0.222 AC: 323719 AN: 1461306 Hom.: 37436 Cov.: 36 AF XY: 0.222 AC XY: 161245 AN XY: 726984

African (AFR) AF: 0.214 AC: 7149 AN: 33456

American (AMR) AF: 0.180 AC: 8069 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 5544 AN: 26124

East Asian (EAS) AF: 0.433 AC: 17163 AN: 39660

South Asian (SAS) AF: 0.220 AC: 18995 AN: 86246

European-Finnish (FIN) AF: 0.232 AC: 12406 AN: 53404

Middle Eastern (MID) AF: 0.202 AC: 1164 AN: 5764

European-Non Finnish (NFE) AF: 0.216 AC: 239753 AN: 1111570

Other (OTH) AF: 0.223 AC: 13476 AN: 60368

GnomAD4 genome AF: 0.221 AC: 33672 AN: 152140 Hom.: 3839 Cov.: 32 AF XY: 0.225 AC XY: 16723 AN XY: 74376

African (AFR) AF: 0.216 AC: 8954 AN: 41490

American (AMR) AF: 0.183 AC: 2796 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 738 AN: 3472

East Asian (EAS) AF: 0.395 AC: 2043 AN: 5166

South Asian (SAS) AF: 0.220 AC: 1058 AN: 4820

European-Finnish (FIN) AF: 0.238 AC: 2519 AN: 10592

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.219 AC: 14899 AN: 67992

Other (OTH) AF: 0.225 AC: 476 AN: 2116

Alfa AF: 0.207 Hom.: 3719

Bravo AF: 0.219

Asia WGS AF: 0.257 AC: 895 AN: 3478

EpiCase AF: 0.218

EpiControl AF: 0.213

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	11	Breast-ovarian cancer, familial, susceptibility to, 2 (11)
-	-	8	not specified (8)
-	-	4	Hereditary breast ovarian cancer syndrome (4)
-	-	3	not provided (3)
-	-	2	Familial cancer of breast (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Fanconi anemia complementation group D1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.7
DANN	Benign	0.75
PhyloP100		0.096
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: rs1799955; hg19: chr13-32929232; COSMIC: COSV66447569;