13-32363351-G-T

Variant names:

• chr13-32363351-G-T
• rs28897747
• NM_000059.4:c.8149G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BA1 BP4 BP5_Strong BS3 BS2

This summary comes from the ClinGen Evidence Repository: The c.8149G>T variant in BRCA2 is a missense variant predicted to cause substitution of Alanine by Serine at amino acid 2717 (p.Ala2717Ser). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥20) or gnomAD v3.1 (non-cancer subset, read depth ≥20) is 0.001751 in the Latino/Admixed American population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of -0.0816, which is below the recommended threshold of 0.18 for predicting no impact on BRCA2 via protein change. SpliceAI predictor score of 0.03 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met). Reported by 3 calibrated studies to exhibit protein function similar to benign control variants (PMIDs: 29988080, 33609447, 32444794) (BS3 met). This variant has been observed in 2 individuals with features considered inconsistent with an FA-associated phenotype, and (Likely) Pathogenic variant seen in trans or variant is homozygous (total score 4 points) (BS2 met; Invitae internal contributor). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 2.288E-117 (based on Cosegregation LR=4.52E-08; Pathology LR=5.249E-08; Family History LR=1.995E-19; Case-Control LR=4.83E-84), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID:Internal lab contributors).In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BP4, BS3, BS2, BP5_Very strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA025471/MONDO:0012933/097

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:38 O:1
• Conservation: PhyloP100: 4.39
• Publications: 44 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 -21 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.8149G>T	p.Ala2717Ser	missense	Exon 18 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.8149G>T	p.Ala2717Ser	missense	Exon 18 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.8149G>T	p.Ala2717Ser	missense	Exon 18 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.8149G>T	p.Ala2717Ser	missense	Exon 18 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.8149G>T	p.Ala2717Ser	missense	Exon 18 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.7780G>T	p.Ala2594Ser	missense	Exon 18 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 195 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00109 AC: 275 AN: 251278 AF XY: 0.00114

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00140 AC: 2053 AN: 1461862 Hom.: 2 Cov.: 31 AF XY: 0.00134 AC XY: 977 AN XY: 727226

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.000917 AC: 41 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00110 AC: 59 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00169 AC: 1877 AN: 1111998

Other (OTH) AF: 0.00108 AC: 65 AN: 60394

GnomAD4 genome AF: 0.00128 AC: 195 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74450

African (AFR) AF: 0.000530 AC: 22 AN: 41546

American (AMR) AF: 0.00235 AC: 36 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00188 AC: 128 AN: 68002

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

Alfa AF: 0.00137 Hom.: 0

Bravo AF: 0.00137

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00116 AC: 141

EpiCase AF: 0.00158

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	12	Breast-ovarian cancer, familial, susceptibility to, 2 (12)
-	1	6	not specified (8)
-	-	6	not provided (6)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	3	Hereditary breast ovarian cancer syndrome (3)
-	-	2	BRCA2-related cancer predisposition (2)
-	1	1	Breast and/or ovarian cancer (2)
-	-	1	BRCA2-related disorder (1)
-	-	1	Fanconi anemia complementation group D1 (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	10
DANN	Uncertain	1.0
Eigen	Benign	0.053
Eigen_PC	Benign	-0.056
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.31	T
PhyloP100		4.4
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.44	N
REVEL	Uncertain	0.54
Sift	Benign	0.12	T
Sift4G	Benign	0.14	T
Vest4		0.38
MVP		0.86
MPC		0.022
ClinPred		0.042	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.34
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs28897747; hg19: chr13-32937488; COSMIC: COSV66460731;