NM_000059.4:c.6848C>A

Variant names:

• chr13-32344564-C-A
• rs80358910
• NM_000059.4:c.6848C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000059.4(BRCA2):​c.6848C>A​(p.Pro2283His) variant causes a missense change. The variant allele was found at a frequency of 0.00000438 in 1,370,992 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2283T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 5.71
• Publications: 11 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):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.6848C>A	p.Pro2283His	missense_variant	Exon 12 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.6848C>A	p.Pro2283His	missense_variant	Exon 12 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.6479C>A	p.Pro2160His	missense_variant	Exon 12 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.6848C>A		non_coding_transcript_exon_variant	Exon 11 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000244 AC: 6 AN: 245672 AF XY: 0.0000225

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000178

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000438 AC: 6 AN: 1370992 Hom.: 0 Cov.: 26 AF XY: 0.00000583 AC XY: 4 AN XY: 686402

African (AFR) AF: 0.00 AC: 0 AN: 31082

American (AMR) AF: 0.000137 AC: 6 AN: 43670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25344

East Asian (EAS) AF: 0.00 AC: 0 AN: 39140

South Asian (SAS) AF: 0.00 AC: 0 AN: 82938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5532

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1032996

Other (OTH) AF: 0.00 AC: 0 AN: 57274

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000866 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2

Feb 22, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with histidine at codon 2283 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 24549055). This variant has been identified in 6/245672 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:2

Jun 29, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with histidine at codon 2283 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 24549055). This variant has been identified in 6/245672 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Mar 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P2283H variant (also known as c.6848C>A), located in coding exon 11 of the BRCA2 gene, results from a C to A substitution at nucleotide position 6848. The proline at codon 2283 is replaced by histidine, an amino acid with similar properties. This variant has been detected in two French breast or ovarian cancer patients (Castera L et al. Eur J Hum Genet. 2014 Nov;22(11):1305-13). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

not specified Uncertain:1

May 08, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.6848C>A (p.Pro2283His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 245672 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6848C>A has been reported in the literature in individuals affected with Hereditary Breast And/or Ovarian Cancer (example: Castera_2014). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24549055). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Oct 23, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.6848C>A (p.Pro2283His) variant has been reported in the published literature in an individual with breast and/or ovarian cancer (PMID: 24549055 (2014)). A large multifactorial analysis study has classified the variant as a variant of uncertain significance (PMID: 31131967 (2019)). The frequency of this variant in the general population, 0.00018 (6/33760 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Familial cancer of breast Uncertain:1

Sep 06, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 2283 of the BRCA2 protein (p.Pro2283His). This variant is present in population databases (rs80358910, gnomAD 0.02%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24549055). ClinVar contains an entry for this variant (Variation ID: 52214). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	0.0030	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	0.44	D
PhyloP100		5.7
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.3	N;N
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.41
MutPred		0.50		Loss of disorder (P = 0.0566);Loss of disorder (P = 0.0566);
MVP		0.96
MPC		0.17
ClinPred		0.60	D
GERP RS		5.0
gMVP		0.38
Mutation Taster		=6/94	disease causing

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: rs80358910; hg19: chr13-32918701;