chr13-32336826-T-C

Variant names:

• chr13-32336826-T-C
• rs397507631
• NM_000059.4:c.2471T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BS1_Supporting BP1_Strong BP5

This summary comes from the ClinGen Evidence Repository: The c.2471T>C variant in BRCA2 is a missense variant predicted to cause substitution of leucine by serine at amino acid 824 (p.Leu824Ser). 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 0.00002053 in the East Asian population, which is within the ENIGMA BRCA1/2 VCEP threshold (>0.00002 to ≤ 0.0001) for BS1_Supporting (BS1_Supporting met). This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using SpliceAI (score 0.01, score threshold <0.1) (BP1_Strong met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.30789 (based on Family History LR=0.30789), within the thresholds for supporting benign evidence (LR ≥0.23 & <0.48) (BP5 met; PMIDs 31853058). In summary, this variant meets the criteria to be classified as a Likely benign variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP1_Strong, BS1_Supporting, BP5). LINK:https://erepo.genome.network/evrepo/ui/classification/CA015397/MONDO:0700269/097

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:5 B:2 O:1
• Conservation: PhyloP100: 0.526
• Publications: 16 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 -6 ACMG points.

• BP1: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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.2471T>C	p.Leu824Ser	missense	Exon 11 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.2471T>C	p.Leu824Ser	missense	Exon 11 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.2471T>C	p.Leu824Ser	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.2471T>C	p.Leu824Ser	missense	Exon 11 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.2471T>C	p.Leu824Ser	missense	Exon 11 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.2102T>C	p.Leu701Ser	missense	Exon 11 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000842 AC: 2 AN: 237562 AF XY: 0.00000778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1450344 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 721018

African (AFR) AF: 0.00 AC: 0 AN: 32538

American (AMR) AF: 0.00 AC: 0 AN: 41606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25570

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 83194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109036

Other (OTH) AF: 0.00 AC: 0 AN: 59880

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	1	Hereditary cancer-predisposing syndrome (3)
-	-	1	BRCA2-related cancer predisposition (1)
-	1	-	Breast-ovarian cancer, familial, susceptibility to, 2 (1)
-	1	-	Hereditary breast ovarian cancer syndrome (1)
-	1	-	not specified (2)
1	-	-	Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.15	N
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.76	T
PhyloP100		0.53
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.26
Sift	Benign	0.036	D
Sift4G	Benign	0.14	T
Vest4		0.43
MutPred		0.53		Gain of disorder (P = 0.021)
MVP		0.86
MPC		0.11
ClinPred		0.43	T
GERP RS		4.4
gMVP		0.44
Mutation Taster		=79/21	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: rs397507631; hg19: chr13-32910963;