13-32379412-G-T

Variant names:

• chr13-32379412-G-T
• rs28897754
• NM_000059.4:c.8850G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000059.4(BRCA2):​c.8850G>T​(p.Lys2950Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000814 in 1,613,836 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K2950E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00075 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:28 O:1
• Conservation: PhyloP100: 2.06
• Publications: 55 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023308098).
• BP6: Variant 13-32379412-G-T is Benign according to our data. Variant chr13-32379412-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 52692.
• BS2: High Homozygotes in GnomAd4 at 3 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.8850G>T	p.Lys2950Asn	missense	Exon 22 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.8850G>T	p.Lys2950Asn	missense	Exon 22 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.8850G>T	p.Lys2950Asn	missense	Exon 22 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.8850G>T	p.Lys2950Asn	missense	Exon 22 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.8850G>T	p.Lys2950Asn	missense	Exon 22 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.8481G>T	p.Lys2827Asn	missense	Exon 22 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 115 AN: 152202 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000738 AC: 185 AN: 250752 AF XY: 0.000634

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000865

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000820 AC: 1199 AN: 1461516 Hom.: 0 Cov.: 31 AF XY: 0.000816 AC XY: 593 AN XY: 727044

African (AFR) AF: 0.0000897 AC: 3 AN: 33458

American (AMR) AF: 0.00172 AC: 77 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000958 AC: 1065 AN: 1111854

Other (OTH) AF: 0.000596 AC: 36 AN: 60370

GnomAD4 genome AF: 0.000755 AC: 115 AN: 152320 Hom.: 3 Cov.: 32 AF XY: 0.000725 AC XY: 54 AN XY: 74496

African (AFR) AF: 0.000120 AC: 5 AN: 41578

American (AMR) AF: 0.00294 AC: 45 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68022

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000853 Hom.: 0

Bravo AF: 0.00101

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000675 AC: 82

EpiCase AF: 0.00109

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	8	Breast-ovarian cancer, familial, susceptibility to, 2 (9)
-	1	7	not specified (9)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	Hereditary breast ovarian cancer syndrome (3)
-	-	3	not provided (3)
-	-	1	BRCA2-related cancer predisposition (1)
-	-	1	BRCA2-related disorder (1)
-	-	1	Breast and/or ovarian cancer (1)
-	1	-	Fanconi anemia complementation group D1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	-0.0088
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.35	T
PhyloP100		2.1
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Vest4		0.38
MutPred		0.69		Loss of ubiquitination at K2950 (P = 0.0051)
MVP		0.86
MPC		0.17
ClinPred		0.051	T
GERP RS		1.8
gMVP		0.49
Mutation Taster		=71/29	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: rs28897754; hg19: chr13-32953549; COSMIC: COSV66455693;