chr13-32332843-A-G

Variant names:

• chr13-32332843-A-G
• rs1801439
• NM_000059.4:c.1365A>G

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.1365A>G​(p.Ser455Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.042 in 1,611,544 control chromosomes in the GnomAD database, including 2,184 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.041 (218 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1966 hom.)
• Consequence: BRCA2 NM_000059.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:33
• Conservation: PhyloP100: 1.04
• Publications: 65 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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 13-32332843-A-G is Benign according to our data. Variant chr13-32332843-A-G is described in ClinVar as Benign. ClinVar VariationId is 125943.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=1.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.106 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.1365A>G	p.Ser455Ser	synonymous	Exon 10 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.1365A>G	p.Ser455Ser	synonymous	Exon 10 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.1365A>G	p.Ser455Ser	synonymous	Exon 10 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.1365A>G	p.Ser455Ser	synonymous	Exon 10 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.1365A>G	p.Ser455Ser	synonymous	Exon 10 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.996A>G	p.Ser332Ser	synonymous	Exon 10 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.0408 AC: 6214 AN: 152202 Hom.: 215 Cov.: 32

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0969

Gnomad ASJ AF: 0.0438

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0147

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.0460

GnomAD2 exomes AF: 0.0523 AC: 12969 AN: 247928 AF XY: 0.0552

Gnomad AFR exome AF: 0.0221

Gnomad AMR exome AF: 0.0718

Gnomad ASJ exome AF: 0.0381

Gnomad EAS exome AF: 0.102

Gnomad FIN exome AF: 0.0154

Gnomad NFE exome AF: 0.0350

Gnomad OTH exome AF: 0.0484

GnomAD4 exome AF: 0.0421 AC: 61373 AN: 1459224 Hom.: 1966 Cov.: 35 AF XY: 0.0447 AC XY: 32417 AN XY: 725722

African (AFR) AF: 0.0204 AC: 678 AN: 33268

American (AMR) AF: 0.0745 AC: 3290 AN: 44140

Ashkenazi Jewish (ASJ) AF: 0.0412 AC: 1071 AN: 26014

East Asian (EAS) AF: 0.119 AC: 4718 AN: 39674

South Asian (SAS) AF: 0.115 AC: 9774 AN: 85284

European-Finnish (FIN) AF: 0.0151 AC: 808 AN: 53368

Middle Eastern (MID) AF: 0.0553 AC: 318 AN: 5750

European-Non Finnish (NFE) AF: 0.0342 AC: 37967 AN: 1111448

Other (OTH) AF: 0.0456 AC: 2749 AN: 60278

GnomAD4 genome AF: 0.0409 AC: 6233 AN: 152320 Hom.: 218 Cov.: 32 AF XY: 0.0436 AC XY: 3248 AN XY: 74490

African (AFR) AF: 0.0214 AC: 889 AN: 41588

American (AMR) AF: 0.0977 AC: 1494 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0438 AC: 152 AN: 3472

East Asian (EAS) AF: 0.0999 AC: 518 AN: 5186

South Asian (SAS) AF: 0.114 AC: 550 AN: 4822

European-Finnish (FIN) AF: 0.0147 AC: 156 AN: 10618

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0344 AC: 2339 AN: 68020

Other (OTH) AF: 0.0479 AC: 101 AN: 2110

Alfa AF: 0.0364 Hom.: 366

Bravo AF: 0.0422

Asia WGS AF: 0.110 AC: 381 AN: 3478

EpiCase AF: 0.0363

EpiControl AF: 0.0390

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	11	Breast-ovarian cancer, familial, susceptibility to, 2 (11)
-	-	10	not specified (10)
-	-	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	-0.62
CADD	Benign	6.0
DANN	Benign	0.56
PhyloP100		1.0
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: rs1801439; hg19: chr13-32906980; COSMIC: COSV66448386;