13-32337362-C-G

Position:

• chr13-32337362-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000059.4(BRCA2):​c.3007C>G​(p.His1003Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,142 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: -0.102

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.3007C>G	p.His1003Asp	missense_variant	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.3007C>G	p.His1003Asp	missense_variant	11/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.2638C>G	p.His880Asp	missense_variant	11/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.3007C>G		non_coding_transcript_exon_variant	10/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 17, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 13, 2019	The p.H1003D variant (also known as c.3007C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 3007. The histidine at codon 1003 is replaced by aspartic acid, an amino acid with similar properties. In one study, this alteration was identified in 1/337 Korean ovarian cancer patients (Lim MC et al. J. Cancer Res. Clin. Oncol., 2009 Nov;135:1593-9). This amino acid position is highly conserved through the hedgehog, but is not conserved in lower species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 15, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 15, 2023	Variant summary: BRCA2 c.3007C>G (p.His1003Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250722 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3007C>G has been reported in the literature in individuals of East Asian ethnicity affected with Hereditary Breast and/or Ovarian Cancer Syndrome (example, Lim_2009, Lee_2018, Ha_2020, Park_2021, Li_2020). At-least one of these studies reported this variant with a final ACMG based classification of likely benign but the evidential basis of this is not explicitly stated (Lee_2018). All other reports include this variant among the VUS listed in the respective studies. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with another pathogenic variant has been reported (BRCA1 c.5470_5477del, p.Ile1824AspfsX3; Li_2020), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33078592, 30415210, 19499246, 34063308, 31396961, 32694901). Five ClinVar submitters (evaluation after 2014) have reported the variant with conflicting assessments: 4 submitters classified the variant as VUS, and 1 submitter classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 27, 2023

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. ClinVar contains an entry for this variant (Variation ID: 236845). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 19499246, 30415210, 33078592). This variant is present in population databases (no rsID available, gnomAD 0.06%). This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 1003 of the BRCA2 protein (p.His1003Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	5.4
DANN	Uncertain	0.99
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.17	N
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-0.90	T
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Uncertain	0.38
Sift	Benign	0.081	T;T
Sift4G	Benign	0.61	T;T
Vest4		0.52
MutPred		0.64		Gain of disorder (P = 0.0931);Gain of disorder (P = 0.0931);
MVP		0.86
MPC		0.030
ClinPred		0.12	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs878853565; hg19: chr13-32911499;