rs41293521

Variant names:

• chr13-32394724-T-C
• rs41293521
• NM_000059.4:c.9292T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM1 BP4_Strong BP6_Very_Strong

The NM_000059.4(BRCA2):​c.9292T>C​(p.Tyr3098His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. Y3098C) has been classified as Uncertain significance. The gene BRCA2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:22 O:1
• Conservation: PhyloP100: 0.618
• Publications: 34 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 -10 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 15 benign, 16 uncertain in NM_000059.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.032249957).
• BP6: Variant 13-32394724-T-C is Benign according to our data. Variant chr13-32394724-T-C is described in ClinVar as Benign. ClinVar VariationId is 38227.Status of the report is reviewed_by_expert_panel, 3 stars.

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.9292T>C	p.Tyr3098His	missense	Exon 25 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.9292T>C	p.Tyr3098His	missense	Exon 25 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.9241T>C	p.Tyr3081His	missense	Exon 25 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.9292T>C	p.Tyr3098His	missense	Exon 25 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.9292T>C	p.Tyr3098His	missense	Exon 25 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.8923T>C	p.Tyr2975His	missense	Exon 25 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000291 AC: 73 AN: 250874 AF XY: 0.000251

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000291

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000221 AC: 323 AN: 1461540 Hom.: 0 Cov.: 31 AF XY: 0.000206 AC XY: 150 AN XY: 727056

African (AFR) AF: 0.0000896 AC: 3 AN: 33474

American (AMR) AF: 0.00103 AC: 46 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53402

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

European-Non Finnish (NFE) AF: 0.000228 AC: 253 AN: 1111808

Other (OTH) AF: 0.000315 AC: 19 AN: 60382

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74514

African (AFR) AF: 0.0000722 AC: 3 AN: 41578

American (AMR) AF: 0.000915 AC: 14 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68036

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000236 Hom.: 1

Bravo AF: 0.000446

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	7	Breast-ovarian cancer, familial, susceptibility to, 2 (9)
-	1	6	not specified (8)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	not provided (2)
-	-	1	BRCA2-related cancer predisposition (1)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	12
DANN	Benign	0.13
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.051	N
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.95	T
PhyloP100		0.62
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.39	N
REVEL	Uncertain	0.45
Sift	Benign	0.78	T
Sift4G	Benign	1.0	T
Vest4		0.35
MVP		0.76
MPC		0.022
ClinPred		0.0033	T
GERP RS		1.6
gMVP		0.36
Mutation Taster		=88/12	polymorphism

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: rs41293521; hg19: chr13-32968861;