rs80358414

Variant names:

• chr13-32332689-A-G
• rs80358414
• NM_000059.4:c.1211A>G
• BRCA2 p.Asn404Ser

Your query was ambiguous. Multiple possible variants found:

• chr13-32332689-A-G
• chr13-32332689-A-T
• chr13-32332689-A-C

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_000059.4(BRCA2):c.1211A>G (p.Asn404Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000137 (AC=2) in the gnomAD database across 1,461,574 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000835. In-silico predictor (REVEL) classifies this variant as likely benign. 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.N404I: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 51082); p.N404= (synonymous): Likely_benign (ClinVar VariationId 2766627, 1 star)

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 2.39
• Publications: 9 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 0 points.

• PM2: Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000835 — very rare for AD+AR gene (base 0.0001, raised to 0.000139 by highest known P/LP ClinVar AF 0.000139) — PM2 moderate.
• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

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.1211A>G	p.Asn404Ser	missense	Exon 10 of 27	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.1211A>G	p.Asn404Ser	missense	Exon 10 of 27	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.1211A>G	p.Asn404Ser	missense	Exon 10 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.1211A>G	p.Asn404Ser	missense	Exon 10 of 27	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.1211A>G	p.Asn404Ser	missense	Exon 10 of 27	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.842A>G	p.Asn281Ser	missense	Exon 10 of 27	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461574 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727066

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111898

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ALFA (dbGaP/dbSNP Allele Frequency Aggregator) AF: 0.00 AC: 0 AN: 16840 Hom.: 0

Local populations

ChinaMAP Phase 1 AF: 0.0000492

Case/control cohorts

Cohort

Cases

Controls

SCHEMA (Schizophrenia)

5 / 102118AF: 0.0000489630

3 / 182912AF: 0.0000164013

Allele 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
-	2	1	Hereditary cancer-predisposing syndrome (3)
-	2	-	Breast-ovarian cancer, familial, susceptibility to, 2 (2)
-	1	-	BRCA2-related disorder (1)
-	1	-	Breast neoplasm (1)
-	1	-	Hereditary breast ovarian cancer syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.65
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.71	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.90	T
PhyloP100		2.4
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.099
Sift	Benign	0.072	T
Sift4G	Benign	0.22	T
VESM-3B	Benign	-1.5
FuncVEP CTI	Benign	0.00049
AlphaGenome AVI	Uncertain	11
GPN-Star LLR		-1.6
GPN-Star score		1.6
Mutation Taster		=90/10	polymorphism

Splicing

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

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: rs80358414;

hg19: chr13-32906826;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar