rs11571707

Variant names:

• chr13-32356461-T-C
• rs11571707
• NM_000059.4:c.7469T>C

Your query was ambiguous. Multiple possible variants found:

• chr13-32356461-T-C
• chr13-32356461-T-A

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.7469T>C​(p.Ile2490Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00481 in 1,614,070 control chromosomes in the GnomAD database, including 495 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2490M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0090 (63 hom., cov: 31)
  • Exomes 𝑓: 0.0044 (432 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:38 O:1
• Conservation: PhyloP100: 0.406
• Publications: 76 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014868975).
• BP6: Variant 13-32356461-T-C is Benign according to our data. Variant chr13-32356461-T-C is described in ClinVar as Benign. ClinVar VariationId is 96852.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0731 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.7469T>C	p.Ile2490Thr	missense	Exon 15 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.7469T>C	p.Ile2490Thr	missense	Exon 15 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.7469T>C	p.Ile2490Thr	missense	Exon 15 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.7469T>C	p.Ile2490Thr	missense	Exon 15 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.7469T>C	p.Ile2490Thr	missense	Exon 15 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.7100T>C	p.Ile2367Thr	missense	Exon 15 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.00897 AC: 1366 AN: 152206 Hom.: 62 Cov.: 31

Gnomad AFR AF: 0.00321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0765

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00211

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0162

GnomAD2 exomes AF: 0.0193 AC: 4864 AN: 251424 AF XY: 0.0151

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00283

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.0130

GnomAD4 exome AF: 0.00438 AC: 6401 AN: 1461746 Hom.: 432 Cov.: 31 AF XY: 0.00383 AC XY: 2787 AN XY: 727188

African (AFR) AF: 0.00128 AC: 43 AN: 33478

American (AMR) AF: 0.129 AC: 5769 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00232 AC: 92 AN: 39698

South Asian (SAS) AF: 0.00163 AC: 141 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000926 AC: 103 AN: 1111878

Other (OTH) AF: 0.00417 AC: 252 AN: 60390

GnomAD4 genome AF: 0.00899 AC: 1370 AN: 152324 Hom.: 63 Cov.: 31 AF XY: 0.0100 AC XY: 746 AN XY: 74496

African (AFR) AF: 0.00320 AC: 133 AN: 41578

American (AMR) AF: 0.0767 AC: 1173 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5192

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68026

Other (OTH) AF: 0.0161 AC: 34 AN: 2116

Alfa AF: 0.00201 Hom.: 27

Bravo AF: 0.0161

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0143 AC: 1737

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	10	Breast-ovarian cancer, familial, susceptibility to, 2 (11)
-	-	7	not specified (8)
-	-	5	Hereditary breast ovarian cancer syndrome (5)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	5	not provided (5)
-	-	3	Familial cancer of breast (3)
-	-	1	BRCA2-related cancer predisposition (1)
-	-	1	Breast and/or ovarian cancer (1)
-	1	-	Breast neoplasm (1)
-	-	1	Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Prostate cancer;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	0.50
DANN	Uncertain	0.98
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.16	N
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.97	T
PhyloP100		0.41
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.73	N
REVEL	Uncertain	0.29
Sift	Benign	0.10	T
Sift4G	Benign	0.088	T
Vest4		0.085
MPC		0.022
ClinPred		0.0039	T
GERP RS		-5.8
gMVP		0.23
Mutation Taster		=98/2	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: rs11571707; hg19: chr13-32930598;