13-32332697-C-G

Position:

• chr13-32332697-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000059.4(BRCA2):​c.1219C>G​(p.Gln407Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 1.22

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19827092).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.1219C>G	p.Gln407Glu	missense_variant	10/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.1219C>G	p.Gln407Glu	missense_variant	10/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.850C>G	p.Gln284Glu	missense_variant	10/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.1219C>G		non_coding_transcript_exon_variant	9/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250212 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135564

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461542 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727056

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 09, 2024	The p.Q407E variant (also known as c.1219C>G), located in coding exon 9 of the BRCA2 gene, results from a C to G substitution at nucleotide position 1219. The glutamine at codon 407 is replaced by glutamic acid, an amino acid with highly similar properties. This variant has been observed in 1/1001 patients with non-mucinous ovarian carcinoma (Alsop K et al. J. Clin. Oncol. 2012 Jul;30:2654-63), in 1/1525 unrelated patients with a personal and/or family history suggestive of Hereditary Breast and/or Ovarian Cancer (Caux-Moncoutier V et al. Hum. Mutat. 2011 Mar;32:325-34), and in 1/898 Greek families who underwent BRCA1/2 testing (Apessos A et al. Cancer Genet, 2018 01;220:1-12). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
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 28, 2021	This missense variant replaces glutamine with glutamic acid at codon 407 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in a few individuals affected with breast or ovarian cancer (PMID: 21120943, 22711857, 31409081) and individual referred for BRCA1/2 screening (PMID: 29310832). This variant has been identified in 3/281592 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 21, 2017

Variant summary: The BRCA2 c.1219C>G (p.Gln407Glu) variant involves the alteration of a non-conserved nucleotide and 3/5 in silico tools predict a damaging outcome for this variant. However, these predictions have yet to be functionally assessed. This variant was found in 2/245832 control chromosomes (gnomAD) at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). Multiple publications have cited the variant in affected individuals, however, with limited information (ie, lack of cosegregation and/or co-occurrence information). In addition, a clinical diagnostic laboratory and reputable database classified this variant as uncertain significance. However, one database does cite the variant to co-occur with a pathogenic BRCA2 variant, c.3599_3600delGT (Cys1200X - Scored DV). Taken together, this variant is classified as a "Variant of Uncertain Significance - Possibly Benign," until additional information becomes available. -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Gln407Glu variant was identified in 2 of 5052 proband chromosomes (frequency: 0.0004) from individuals or families with breast or ovarian cancer (Alsop 2012, Caux-Moncoutier 2011). The variant was also identified in dbSNP (ID: rs781079248) as "With Pathogenic, Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics and Color), LOVD 3.0 (1x), and in UMD-LSDB (1x as unclassified variant). The variant was identified in control databases in 2 of 245832 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 2 of 111520 chromosomes (freq: 0.00002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Gln407 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

BRCA2-related cancer predisposition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Mar 05, 2024

This missense variant replaces glutamine with glutamic acid at codon 407 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in a few individuals affected with breast or ovarian cancer (PMID: 21120943, 22711857, 31409081) and individual referred for BRCA1/2 screening (PMID: 29310832). This variant has been identified in 3/281592 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. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 407 of the BRCA2 protein (p.Gln407Glu). This variant is present in population databases (rs781079248, gnomAD 0.002%). This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 21120943, 22711857, 29310832). ClinVar contains an entry for this variant (Variation ID: 441308). 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 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	0.071
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	0.97
Eigen	Benign	0.017
Eigen_PC	Benign	-0.041
FATHMM_MKL	Benign	0.54	D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.92	T
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.72	N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0070	D;D
Sift4G	Benign	0.25	T;T
Vest4		0.29
MutPred		0.22		Gain of ubiquitination at K410 (P = 0.0764);Gain of ubiquitination at K410 (P = 0.0764);
MVP		0.91
MPC		0.024
ClinPred		0.19	T
GERP RS		3.8
gMVP		0.15

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: rs781079248; hg19: chr13-32906834;