rs80358969

Variant names:

• chr13-32356456-A-C
• rs80358969
• NM_000059.4:c.7464A>C
• BRCA2 p.Arg2488Ser

Your query was ambiguous. Multiple possible variants found:

• chr13-32356456-A-C
• chr13-32356456-A-G

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+3 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 3 classification points (ACMG Germline Pathogenicity v2019). PM2PP3

The NM_000059.4(BRCA2):c.7464A>C (p.Arg2488Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,704 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R2488G: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 462440); p.R2488K: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 52336); p.R2488= (synonymous): Likely_benign (ClinVar VariationId 4215296, 1 star); p.R2488= (synonymous): Likely_benign (ClinVar VariationId 3669829, 1 star); p.R2488T: Likely_benign (ClinVar VariationId 1759029, 1 star)

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:1
• Conservation: PhyloP100: 3.73
• Publications: 8 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• 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

Classification according to ACMG Germline Pathogenicity v2019

Specifications for BRCA2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 3 points.

• PM2: Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AD+AR gene (base 0.0001, raised to 0.000139 by highest known P/LP ClinVar AF 0.000139) — PM2 moderate.
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.7464A>C	p.Arg2488Ser	missense	Exon 15 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.7464A>C	p.Arg2488Ser	missense	Exon 15 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.7464A>C	p.Arg2488Ser	missense	Exon 15 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.7464A>C	p.Arg2488Ser	missense	Exon 15 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.7464A>C	p.Arg2488Ser	missense	Exon 15 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.7095A>C	p.Arg2365Ser	missense	Exon 15 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes					31
GnomAD2 exomes	0.00000398	1		251420
GnomAD4 exome	6.84e-7	1	0	1461704	31
GnomAD4 genome					31

Showing 4 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000147	1	67860	0.00	0	133308

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	Breast-ovarian cancer, familial, susceptibility to, 2 (3)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	2	-	not provided (2)
-	1	-	BRCA2-related cancer predisposition (1)
-	1	-	Familial cancer of breast (1)
-	1	-	Fanconi anemia complementation group D1 (1)
-	1	-	Hereditary breast ovarian cancer syndrome (1)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Pathogenic	-	25
AlphaMissense	Pathogenic	-	0.81
BayesDel_addAF	Pathogenic	D	0.26
BayesDel_noAF	Uncertain	-	0.13
CADD	Uncertain	-	23
DANN	Uncertain	-	1.0
Eigen	Uncertain	-	0.46
Eigen_PC	Uncertain	-	0.36
FATHMM_MKL	Pathogenic	D	0.97
FuncVEP CTI	Benign	-	0.23
GPN-Star LLR	N/A	-	-6.3
GPN-Star score	N/A	-	6.3
M_CAP	Uncertain	D	0.22
MetaRNN	Pathogenic	D	0.84
MetaSVM	Uncertain	D	0.31
Mutation Taster	N/A	polymorphism	53/47
PhyloP100	Uncertain	-	3.7
PrimateAI	Benign	T	0.39
PROVEAN	Benign	N	-1.8
REVEL	Pathogenic	-	0.65
Sift	Uncertain	D	0.0010
Sift4G	Uncertain	D	0.0030
VESM-3B	Benign	-	-6.4

Showing 23 of 23 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.0
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs80358969;

hg19: chr13-32930593;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar