rs80359150

Variant names:

• chr13-32379768-G-A
• rs80359150
• NM_000059.4:c.8972G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-32379768-G-A
• chr13-32379768-G-C
• chr13-32379768-G-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP4 BP6_Very_Strong

The NM_000059.4(BRCA2):​c.8972G>A​(p.Arg2991His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000385 in 1,611,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2991C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:12
• Conservation: PhyloP100: 7.22
• 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 -7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 26 uncertain in NM_000059.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.35748103).
• BP6: Variant 13-32379768-G-A is Benign according to our data. Variant chr13-32379768-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 38200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.8972G>A	p.Arg2991His	missense	Exon 23 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.8972G>A	p.Arg2991His	missense	Exon 23 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406719.1		c.8876G>A	p.Arg2959His	missense	Exon 22 of 26	NP_001393648.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.8972G>A	p.Arg2991His	missense	Exon 23 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.8972G>A	p.Arg2991His	missense	Exon 23 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.8603G>A	p.Arg2868His	missense	Exon 23 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152002 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000837 AC: 21 AN: 250784 AF XY: 0.0000811

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000404 AC: 59 AN: 1459692 Hom.: 0 Cov.: 31 AF XY: 0.0000482 AC XY: 35 AN XY: 726280

African (AFR) AF: 0.0000299 AC: 1 AN: 33428

American (AMR) AF: 0.000335 AC: 15 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39644

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1110098

Other (OTH) AF: 0.0000497 AC: 3 AN: 60322

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152002 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74254

African (AFR) AF: 0.00 AC: 0 AN: 41372

American (AMR) AF: 0.0000656 AC: 1 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000107 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	3	Breast-ovarian cancer, familial, susceptibility to, 2 (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	Hereditary breast ovarian cancer syndrome (2)
-	-	2	not specified (2)
-	-	1	Familial cancer of breast;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	-0.13	T
PhyloP100		7.2
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Vest4		0.50
MVP		0.89
MPC		0.17
ClinPred		0.33	T
GERP RS		4.8
gMVP		0.59
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.11		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: rs80359150; hg19: chr13-32953905; COSMIC: COSV101204253; COSMIC: COSV101204253;