rs766173

Variant names:

• chr13-32332343-A-C
• rs766173
• NM_000059.4:c.865A>C

Your query was ambiguous. Multiple possible variants found:

• chr13-32332343-A-C
• chr13-32332343-A-G
• chr13-32332343-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.865A>C​(p.Asn289His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0418 in 1,598,150 control chromosomes in the GnomAD database, including 2,166 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N289S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.041 (218 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1948 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel B:39 O:1
• Conservation: PhyloP100: 0.498
• Publications: 151 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=0.0015439987).
• BP6: Variant 13-32332343-A-C is Benign according to our data. Variant chr13-32332343-A-C is described in ClinVar as Benign. ClinVar VariationId is 41567.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.106 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.865A>C	p.Asn289His	missense	Exon 10 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.865A>C	p.Asn289His	missense	Exon 10 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.865A>C	p.Asn289His	missense	Exon 10 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.865A>C	p.Asn289His	missense	Exon 10 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.865A>C	p.Asn289His	missense	Exon 10 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.496A>C	p.Asn166His	missense	Exon 10 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.0409 AC: 6221 AN: 152198 Hom.: 215 Cov.: 32

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0970

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.0463

GnomAD2 exomes AF: 0.0521 AC: 12475 AN: 239502 AF XY: 0.0548

Gnomad AFR exome AF: 0.0222

Gnomad AMR exome AF: 0.0731

Gnomad ASJ exome AF: 0.0383

Gnomad EAS exome AF: 0.103

Gnomad FIN exome AF: 0.0154

Gnomad NFE exome AF: 0.0350

Gnomad OTH exome AF: 0.0495

GnomAD4 exome AF: 0.0419 AC: 60573 AN: 1445834 Hom.: 1948 Cov.: 30 AF XY: 0.0445 AC XY: 31960 AN XY: 719010

African (AFR) AF: 0.0205 AC: 668 AN: 32626

American (AMR) AF: 0.0752 AC: 3144 AN: 41798

Ashkenazi Jewish (ASJ) AF: 0.0411 AC: 1056 AN: 25664

East Asian (EAS) AF: 0.119 AC: 4709 AN: 39582

South Asian (SAS) AF: 0.115 AC: 9497 AN: 82778

European-Finnish (FIN) AF: 0.0151 AC: 805 AN: 53242

Middle Eastern (MID) AF: 0.0560 AC: 318 AN: 5674

European-Non Finnish (NFE) AF: 0.0341 AC: 37654 AN: 1104720

Other (OTH) AF: 0.0456 AC: 2722 AN: 59750

GnomAD4 genome AF: 0.0410 AC: 6240 AN: 152316 Hom.: 218 Cov.: 32 AF XY: 0.0436 AC XY: 3248 AN XY: 74476

African (AFR) AF: 0.0213 AC: 887 AN: 41570

American (AMR) AF: 0.0978 AC: 1496 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0441 AC: 153 AN: 3468

East Asian (EAS) AF: 0.100 AC: 520 AN: 5192

South Asian (SAS) AF: 0.114 AC: 550 AN: 4820

European-Finnish (FIN) AF: 0.0148 AC: 157 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0344 AC: 2341 AN: 68028

Other (OTH) AF: 0.0482 AC: 102 AN: 2116

Alfa AF: 0.0348 Hom.: 321

Bravo AF: 0.0423

TwinsUK AF: 0.0299 AC: 111

ALSPAC AF: 0.0324 AC: 125

ESP6500AA AF: 0.0202 AC: 89

ESP6500EA AF: 0.0368 AC: 316

ExAC AF: 0.0515 AC: 6246

Asia WGS AF: 0.110 AC: 380 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	12	Breast-ovarian cancer, familial, susceptibility to, 2 (12)
-	-	10	not specified (11)
-	-	5	not provided (5)
-	-	4	Hereditary breast ovarian cancer syndrome (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	Familial cancer of breast (2)
-	-	1	Breast carcinoma (1)
-	-	1	Fanconi anemia complementation group D1 (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	0.086
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Uncertain	0.99
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.10	N
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.87	T
PhyloP100		0.50
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.086
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.046	D
Vest4		0.12
MPC		0.022
ClinPred		0.010	T
GERP RS		1.7
gMVP		0.12
Mutation Taster		=96/4	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: rs766173; hg19: chr13-32906480; COSMIC: COSV66448377;