rs28897708

Variant names:

• chr13-32332992-T-C
• rs28897708
• NM_000059.4:c.1514T>C

Your query was ambiguous. Multiple possible variants found:

• chr13-32332992-T-C
• chr13-32332992-T-A

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.1514T>C​(p.Ile505Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000988 in 1,593,866 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I505M) has been classified as Likely benign. The gene BRCA2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (1 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:33
• Conservation: PhyloP100: 0.420
• Publications: 39 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=0.00998956).
• BP6: Variant 13-32332992-T-C is Benign according to our data. Variant chr13-32332992-T-C is described in ClinVar as Benign. ClinVar VariationId is 41542.Status of the report is reviewed_by_expert_panel, 3 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.1514T>C	p.Ile505Thr	missense	Exon 10 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.1514T>C	p.Ile505Thr	missense	Exon 10 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.1514T>C	p.Ile505Thr	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.1514T>C	p.Ile505Thr	missense	Exon 10 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.1514T>C	p.Ile505Thr	missense	Exon 10 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.1145T>C	p.Ile382Thr	missense	Exon 10 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.000716 AC: 109 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000802 AC: 185 AN: 230618 AF XY: 0.000825

Gnomad AFR exome AF: 0.000447

Gnomad AMR exome AF: 0.000172

Gnomad ASJ exome AF: 0.00542

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00115

Gnomad NFE exome AF: 0.000900

Gnomad OTH exome AF: 0.000913

GnomAD4 exome AF: 0.00102 AC: 1466 AN: 1441568 Hom.: 1 Cov.: 35 AF XY: 0.000983 AC XY: 704 AN XY: 716416

African (AFR) AF: 0.000157 AC: 5 AN: 31920

American (AMR) AF: 0.000206 AC: 8 AN: 38882

Ashkenazi Jewish (ASJ) AF: 0.00440 AC: 110 AN: 25026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.0000492 AC: 4 AN: 81268

European-Finnish (FIN) AF: 0.00111 AC: 59 AN: 52946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5610

European-Non Finnish (NFE) AF: 0.00110 AC: 1217 AN: 1106878

Other (OTH) AF: 0.00106 AC: 63 AN: 59414

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000685 AC XY: 51 AN XY: 74472

African (AFR) AF: 0.000193 AC: 8 AN: 41558

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68026

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.000635

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000717 AC: 87

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	10	Breast-ovarian cancer, familial, susceptibility to, 2 (10)
-	1	7	not specified (8)
-	-	5	not provided (5)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	Hereditary breast ovarian cancer syndrome (3)
-	-	1	BRCA2-related cancer predisposition (1)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Breast neoplasm (1)
-	-	1	Fanconi anemia complementation group D1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	8.6
DANN	Benign	0.87
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.12	N
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.86	T
PhyloP100		0.42
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.22
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.047	D
Vest4		0.41
MVP		0.89
MPC		0.023
ClinPred		0.029	T
GERP RS		4.1
gMVP		0.096
Mutation Taster		=94/6	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: rs28897708; hg19: chr13-32907129;