rs11571610

Variant names:

• chr13-32325251-A-C
• rs11571610
• NM_000059.4:c.425+67A>C

Your query was ambiguous. Multiple possible variants found:

• chr13-32325251-A-C
• chr13-32325251-A-T

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.425+67A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0437 in 1,200,608 control chromosomes in the GnomAD database, including 1,783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.041 (222 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1561 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:13
• Conservation: PhyloP100: 1.98
• Publications: 19 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=-0.79).
• BP6: Variant 13-32325251-A-C is Benign according to our data. Variant chr13-32325251-A-C is described in ClinVar as Benign. ClinVar VariationId is 126095.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.107 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.425+67A>C		intron	N/A	NP_000050.3
	BRCA2	NM_001432077.1		c.425+67A>C		intron	N/A	NP_001419006.1
	BRCA2	NM_001406720.1		c.425+67A>C		intron	N/A	NP_001393649.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.425+67A>C		intron	N/A	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.425+67A>C		intron	N/A	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.56+67A>C		intron	N/A	ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.0410 AC: 6237 AN: 152176 Hom.: 219 Cov.: 32

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0980

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.0478

GnomAD4 exome AF: 0.0441 AC: 46224 AN: 1048314 Hom.: 1561 AF XY: 0.0470 AC XY: 24918 AN XY: 530522

African (AFR) AF: 0.0210 AC: 503 AN: 23898

American (AMR) AF: 0.0800 AC: 2655 AN: 33202

Ashkenazi Jewish (ASJ) AF: 0.0416 AC: 936 AN: 22502

East Asian (EAS) AF: 0.123 AC: 4112 AN: 33564

South Asian (SAS) AF: 0.117 AC: 7907 AN: 67808

European-Finnish (FIN) AF: 0.0153 AC: 617 AN: 40280

Middle Eastern (MID) AF: 0.0611 AC: 209 AN: 3420

European-Non Finnish (NFE) AF: 0.0349 AC: 27118 AN: 777488

Other (OTH) AF: 0.0470 AC: 2167 AN: 46152

GnomAD4 genome AF: 0.0411 AC: 6256 AN: 152294 Hom.: 222 Cov.: 32 AF XY: 0.0437 AC XY: 3256 AN XY: 74470

African (AFR) AF: 0.0213 AC: 886 AN: 41574

American (AMR) AF: 0.0987 AC: 1509 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0441 AC: 153 AN: 3470

East Asian (EAS) AF: 0.100 AC: 519 AN: 5184

South Asian (SAS) AF: 0.115 AC: 554 AN: 4832

European-Finnish (FIN) AF: 0.0144 AC: 153 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0344 AC: 2343 AN: 68018

Other (OTH) AF: 0.0497 AC: 105 AN: 2114

Alfa AF: 0.0351 Hom.: 36

Bravo AF: 0.0425

Asia WGS AF: 0.109 AC: 376 AN: 3468

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	4	Breast-ovarian cancer, familial, susceptibility to, 2 (5)
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Familial cancer of breast (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.84
PhyloP100		2.0
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: rs11571610; hg19: chr13-32899388;