rs80358589

Variant names:

• chr13-32337800-A-G
• rs80358589
• NM_000059.4:c.3445A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-32337800-A-G
• chr13-32337800-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000059.4(BRCA2):​c.3445A>G​(p.Met1149Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000669 in 1,614,072 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1149L) has been classified as Likely benign. The gene BRCA2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:24 O:1
• Conservation: PhyloP100: 0.300
• Publications: 22 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065045655).
• BP6: Variant 13-32337800-A-G is Benign according to our data. Variant chr13-32337800-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 51465.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.3445A>G	p.Met1149Val	missense	Exon 11 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.3445A>G	p.Met1149Val	missense	Exon 11 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.3445A>G	p.Met1149Val	missense	Exon 11 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.3445A>G	p.Met1149Val	missense	Exon 11 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.3445A>G	p.Met1149Val	missense	Exon 11 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.3076A>G	p.Met1026Val	missense	Exon 11 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000167 AC: 42 AN: 251012 AF XY: 0.000118

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00136

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000554 AC: 81 AN: 1461764 Hom.: 0 Cov.: 35 AF XY: 0.0000550 AC XY: 40 AN XY: 727178

African (AFR) AF: 0.000269 AC: 9 AN: 33468

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000529 AC: 21 AN: 39688

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111946

Other (OTH) AF: 0.000464 AC: 28 AN: 60390

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74490

African (AFR) AF: 0.000337 AC: 14 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15302

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

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000200 Hom.: 1

Bravo AF: 0.000125

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000214 AC: 26

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	4	Breast-ovarian cancer, familial, susceptibility to, 2 (5)
-	1	3	Hereditary breast ovarian cancer syndrome (4)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	4	not provided (4)
-	-	2	not specified (3)
-	-	1	BRCA2-related cancer predisposition (1)
-	-	1	BRCA2-related disorder (1)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Carcinoma of esophagus (1)
-	-	1	Familial cancer of breast (1)
-	-	1	Fanconi anemia (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	0.42
DANN	Benign	0.33
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.083	N
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-0.94	T
PhyloP100		0.30
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.33
Sift	Benign	0.21	T
Sift4G	Benign	1.0	T
Vest4		0.21
MVP		0.60
MPC		0.020
ClinPred		0.015	T
GERP RS		-1.4
gMVP		0.13
Mutation Taster		=28/72	disease causing

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: rs80358589; hg19: chr13-32911937;