rs2320236

Variant names:

• chr13-32336191-T-C
• rs2320236
• NM_000059.4:c.1910-74T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000059.4(BRCA2):​c.1910-74T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,485,862 control chromosomes in the GnomAD database, including 27,614 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3028 hom., cov: 32)
  • Exomes 𝑓: 0.19 (24586 hom.)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: 1.70
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 13-32336191-T-C is Benign according to our data. Variant chr13-32336191-T-C is described in ClinVar as Benign. ClinVar VariationId is 209687.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.1910-74T>C		intron_variant	Intron 10 of 26	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.1910-74T>C		intron_variant	Intron 10 of 26	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.1541-74T>C		intron_variant	Intron 10 of 26	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.1910-74T>C		intron_variant	Intron 9 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29544 AN: 152058 Hom.: 3023 Cov.: 32

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.0825

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.185

GnomAD4 exome AF: 0.188 AC: 251058 AN: 1333686 Hom.: 24586 AF XY: 0.186 AC XY: 122838 AN XY: 660080

African (AFR) AF: 0.210 AC: 6264 AN: 29780

American (AMR) AF: 0.225 AC: 6854 AN: 30488

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 3608 AN: 21348

East Asian (EAS) AF: 0.0579 AC: 2249 AN: 38816

South Asian (SAS) AF: 0.134 AC: 9410 AN: 70098

European-Finnish (FIN) AF: 0.257 AC: 12838 AN: 50002

Middle Eastern (MID) AF: 0.144 AC: 535 AN: 3718

European-Non Finnish (NFE) AF: 0.192 AC: 198875 AN: 1033992

Other (OTH) AF: 0.188 AC: 10425 AN: 55444

GnomAD4 genome AF: 0.194 AC: 29582 AN: 152176 Hom.: 3028 Cov.: 32 AF XY: 0.194 AC XY: 14451 AN XY: 74396

African (AFR) AF: 0.213 AC: 8838 AN: 41516

American (AMR) AF: 0.198 AC: 3034 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 571 AN: 3472

East Asian (EAS) AF: 0.0831 AC: 431 AN: 5186

South Asian (SAS) AF: 0.126 AC: 608 AN: 4826

European-Finnish (FIN) AF: 0.253 AC: 2670 AN: 10568

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.188 AC: 12801 AN: 68002

Other (OTH) AF: 0.184 AC: 388 AN: 2110

Alfa AF: 0.190 Hom.: 5499

Bravo AF: 0.194

Asia WGS AF: 0.138 AC: 479 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

Nov 01, 2017

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Jan 12, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.07343 (Asian), 0.2703 (African), 0.2018 (European), derived from 1000 genomes (2012-04-30). -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary cancer-predisposing syndrome Benign:1

Nov 19, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	12
DANN	Benign	0.80
PhyloP100		1.7
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: rs2320236; hg19: chr13-32910328;