rs45574331

Variant names:

• chr13-32354870-G-C
• rs45574331
• NM_000059.4:c.7017G>C

Your query was ambiguous. Multiple possible variants found:

• chr13-32354870-G-C
• chr13-32354870-G-A
• chr13-32354870-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000059.4(BRCA2):​c.7017G>C​(p.Lys2339Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,583,632 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 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. K2339E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0072 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (9 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:36 O:1
• Conservation: PhyloP100: 0.0550
• Publications: 24 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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 40 uncertain in NM_000059.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.005285591).
• BP6: Variant 13-32354870-G-C is Benign according to our data. Variant chr13-32354870-G-C is described in ClinVar as Benign. ClinVar VariationId is 52249.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00719 (1095/152288) while in subpopulation AFR AF = 0.025 (1039/41562). AF 95% confidence interval is 0.0237. There are 15 homozygotes in GnomAd4. There are 524 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AD,AR gene

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.7017G>C	p.Lys2339Asn	missense	Exon 14 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.7017G>C	p.Lys2339Asn	missense	Exon 14 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.7017G>C	p.Lys2339Asn	missense	Exon 14 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.7017G>C	p.Lys2339Asn	missense	Exon 14 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.7017G>C	p.Lys2339Asn	missense	Exon 14 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.6648G>C	p.Lys2216Asn	missense	Exon 14 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.00720 AC: 1096 AN: 152170 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

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: 0.0000588

Gnomad OTH AF: 0.00671

GnomAD2 exomes AF: 0.00177 AC: 443 AN: 250504 AF XY: 0.00133

Gnomad AFR exome AF: 0.0253

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000706 AC: 1010 AN: 1431344 Hom.: 9 Cov.: 29 AF XY: 0.000619 AC XY: 442 AN XY: 713830

African (AFR) AF: 0.0245 AC: 803 AN: 32760

American (AMR) AF: 0.00123 AC: 55 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25954

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39512

South Asian (SAS) AF: 0.000117 AC: 10 AN: 85564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000701 AC: 4 AN: 5708

European-Non Finnish (NFE) AF: 0.0000387 AC: 42 AN: 1084368

Other (OTH) AF: 0.00160 AC: 95 AN: 59386

GnomAD4 genome AF: 0.00719 AC: 1095 AN: 152288 Hom.: 15 Cov.: 32 AF XY: 0.00704 AC XY: 524 AN XY: 74452

African (AFR) AF: 0.0250 AC: 1039 AN: 41562

American (AMR) AF: 0.00248 AC: 38 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68034

Other (OTH) AF: 0.00664 AC: 14 AN: 2108

Alfa AF: 0.000989 Hom.: 0

Bravo AF: 0.00804

ESP6500AA AF: 0.0239 AC: 105

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00230 AC: 279

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	7	Breast-ovarian cancer, familial, susceptibility to, 2 (8)
-	-	8	not specified (9)
-	-	5	Hereditary breast ovarian cancer syndrome (5)
-	-	5	not provided (5)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	2	Familial cancer of breast (2)
-	-	1	BRCA2-related cancer predisposition (1)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Fanconi anemia complementation group D1 (1)
-	-	1	Malignant tumor of breast (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	0.21
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	5.2
DANN	Benign	0.93
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.067	N
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.75	T
PhyloP100		0.055
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.18
Sift	Benign	0.050	D
Sift4G	Uncertain	0.032	D
Vest4		0.20
MutPred		0.25		Loss of ubiquitination at K2339 (P = 0.0081)
MVP		0.84
MPC		0.022
ClinPred		0.011	T
GERP RS		-2.0
gMVP		0.35
Mutation Taster		=98/2	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: rs45574331; hg19: chr13-32929007; COSMIC: COSV99061758;