rs80359034

Variant names:

• chr13-32319088-A-G
• rs80359034
• NM_000059.4:c.79A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-32319088-A-G
• chr13-32319088-A-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS2

The NM_000059.4(BRCA2):​c.79A>G​(p.Ile27Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,460,468 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I27M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000018 (2 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:5
• Conservation: PhyloP100: 0.353
• Publications: 19 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: Likely_benign. The variant received -5 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 38 uncertain in NM_000059.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.12545416).
• BP6: Variant 13-32319088-A-G is Benign according to our data. Variant chr13-32319088-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 52467.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.79A>G	p.Ile27Val	missense	Exon 3 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.79A>G	p.Ile27Val	missense	Exon 3 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.79A>G	p.Ile27Val	missense	Exon 3 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.79A>G	p.Ile27Val	missense	Exon 3 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.79A>G	p.Ile27Val	missense	Exon 3 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.-291A>G		5_prime_UTR	Exon 3 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250402 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1460468 Hom.: 2 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 726588

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.0000224 AC: 1 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1110920

Other (OTH) AF: 0.0000331 AC: 2 AN: 60346

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000340 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	Breast-ovarian cancer, familial, susceptibility to, 2 (3)
-	2	1	not provided (3)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	-	1	BRCA2-related cancer predisposition (1)
-	-	1	BRCA2-related disorder (1)
-	1	-	Familial cancer of breast (1)
-	1	-	Hereditary breast ovarian cancer syndrome (1)
-	1	-	Malignant tumor of breast (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.3
DANN	Uncertain	1.0
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.75	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.93	T
PhyloP100		0.35
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.057
Sift	Benign	0.073	T
Sift4G	Benign	0.070	T
Vest4		0.26
MutPred		0.18		Loss of catalytic residue at I27 (P = 0.0823)
MVP		0.72
MPC		0.084
ClinPred		0.68	D
GERP RS		3.2
gMVP		0.23
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs80359034; hg19: chr13-32893225;