rs28897727

Variant names:

• chr13-32338613-G-T
• rs28897727
• NM_000059.4:c.4258G>T

Your query was ambiguous. Multiple possible variants found:

• chr13-32338613-G-T
• chr13-32338613-G-A
• chr13-32338613-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000059.4(BRCA2):​c.4258G>T​(p.Asp1420Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00643 in 1,596,994 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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. D1420V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0060 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (46 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel B:41 O:2
• Conservation: PhyloP100: 0.305
• Publications: 81 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073898137).
• BP6: Variant 13-32338613-G-T is Benign according to our data. Variant chr13-32338613-G-T is described in ClinVar as Benign. ClinVar VariationId is 41549.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00599 (912/152226) while in subpopulation NFE AF = 0.00777 (528/67976). AF 95% confidence interval is 0.00722. There are 9 homozygotes in GnomAd4. There are 505 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.4258G>T	p.Asp1420Tyr	missense	Exon 11 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.4258G>T	p.Asp1420Tyr	missense	Exon 11 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.4258G>T	p.Asp1420Tyr	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.4258G>T	p.Asp1420Tyr	missense	Exon 11 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.4258G>T	p.Asp1420Tyr	missense	Exon 11 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.3889G>T	p.Asp1297Tyr	missense	Exon 11 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.00600 AC: 913 AN: 152108 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00777

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00650 AC: 1589 AN: 244580 AF XY: 0.00682

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00153

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0186

Gnomad NFE exome AF: 0.00744

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00648 AC: 9355 AN: 1444768 Hom.: 46 Cov.: 35 AF XY: 0.00667 AC XY: 4771 AN XY: 715584

African (AFR) AF: 0.00110 AC: 36 AN: 32840

American (AMR) AF: 0.00210 AC: 91 AN: 43304

Ashkenazi Jewish (ASJ) AF: 0.00124 AC: 32 AN: 25852

East Asian (EAS) AF: 0.0000509 AC: 2 AN: 39304

South Asian (SAS) AF: 0.00823 AC: 687 AN: 83444

European-Finnish (FIN) AF: 0.0173 AC: 922 AN: 53222

Middle Eastern (MID) AF: 0.00527 AC: 30 AN: 5692

European-Non Finnish (NFE) AF: 0.00660 AC: 7265 AN: 1101510

Other (OTH) AF: 0.00487 AC: 290 AN: 59600

GnomAD4 genome AF: 0.00599 AC: 912 AN: 152226 Hom.: 9 Cov.: 33 AF XY: 0.00679 AC XY: 505 AN XY: 74422

African (AFR) AF: 0.00147 AC: 61 AN: 41564

American (AMR) AF: 0.00216 AC: 33 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00704 AC: 34 AN: 4830

European-Finnish (FIN) AF: 0.0225 AC: 238 AN: 10590

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00777 AC: 528 AN: 67976

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00655 Hom.: 8

Bravo AF: 0.00417

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00115 AC: 5

ESP6500EA AF: 0.00538 AC: 46

ExAC AF: 0.00671 AC: 814

Asia WGS AF: 0.00491 AC: 17 AN: 3474

EpiCase AF: 0.00641

EpiControl AF: 0.00753

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	13	Breast-ovarian cancer, familial, susceptibility to, 2 (14)
-	-	9	not specified (10)
-	-	6	not provided (6)
-	-	5	Hereditary breast ovarian cancer syndrome (5)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Familial cancer of breast (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	13
DANN	Uncertain	0.99
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.50	N
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.91	T
PhyloP100		0.30
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Benign	0.15
Sift	Benign	0.030	D
Sift4G	Uncertain	0.0070	D
Vest4		0.35
MVP		0.81
MPC		0.024
ClinPred		0.012	T
GERP RS		1.1
gMVP		0.27
Mutation Taster		=99/1	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: rs28897727; hg19: chr13-32912750; COSMIC: COSV66451253;