13-32379872-C-G

Position:

• chr13-32379872-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000059.4(BRCA2):​c.9076C>G​(p.Gln3026Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,188 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:4
• Conservation: PhyloP100: 7.31

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 13-32379872-C-G is Benign according to our data. Variant chr13-32379872-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52742.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9076C>G	p.Gln3026Glu	missense_variant	23/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9076C>G	p.Gln3026Glu	missense_variant	23/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8707C>G	p.Gln2903Glu	missense_variant	23/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1134C>G		non_coding_transcript_exon_variant	22/26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*1134C>G		3_prime_UTR_variant	22/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000800 AC: 2 AN: 250082 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135226

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461188 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726940

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	PM2(Supporting)+BS3(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is denoted BRCA2 c.9076C>G at the cDNA level, p.Gln3026Glu (Q3026E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAG>GAG). Using alternate nomenclature, this variant has been previously published as BRCA2 9304C>G. This variant has been observed in at least two individuals with suspected Hereditary Breast and Ovarian Cancer (Kauff 2002, Schenkel 2016). BRCA2 Gln3026Glu was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamine and Glutamic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Gln3026Glu occurs at a position that is not conserved and is located in the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Gln3026Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Gln3026Glu variant was identified in 2 of 620 proband chromosomes (frequency: 0.003) from individuals or families with hereditary breast and ovarian cancer (Kauff 2002, Schenkel 2016). The variant was also identified in following databases: dbSNP (ID: rs80359159) as "Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry genetics, GeneDx, BIC), Clinvitae, and LOVD 3.0 (as inconclusive). The variant was not identified in COGR, Cosmic, MutDB, UMD-LSDB, BIC Database, ARUP Laboratories, or Zhejiang University Database. The variant was identified in control databases in 2 of 244944 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). It was observed in the European (Non-Finnish) population in 2 of 110742 chromosomes (freq: 0.00002), but not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. One study classified the variant as uncertain significance based on a protein likelihood ratio model (Karchin 2008). The variant was also reported in a study of the incidence of non-founder BRCA1 and BRCA2 mutations in high risk Ashkenazi breast and ovarian cancer families, where it was also classified as a variant of uncertain clinical significance (Kauff 2002). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Gln3026 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. 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. -

Hereditary breast ovarian cancer syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Jan 05, 2024	. According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose this criterium: BP4 (supporting benign): BayesDEL:0.00500399 and spliceAI: BRCA2: 0.07 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 3026 of the BRCA2 protein (p.Gln3026Glu). This variant is present in population databases (rs80359159, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer, melanoma, and/or ovarian cancer (PMID: 12161607, 27376475, 29625052, 31161121, 34178674, 36451132). This variant is also known as c.9304C>G. ClinVar contains an entry for this variant (Variation ID: 52742). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 29884841, 35736817). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 06, 2019	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 06, 2021	This missense variant replaces glutamine with glutamic acid at codon 3026 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). A functional study reported that this variant has no impact on homology-directed DNA repair (PMID: 29884841). This variant has been detected in at least four individuals affected with breast or ovarian cancer (PMID: 12161607, 31161121, 33471991, 34178674; Leiden Open Variation Database DB-ID BRCA2_000398), an individual affected with skin cancer (PMID: 29625052) and a family suspected of being affected with hereditary breast and ovarian cancer (PMID: 27376475). This variant has been identified in 2/250082 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 Benign:2

Benign, no assertion criteria provided	research	King Laboratory, University of Washington	Sep 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 13, 2021	Variant summary: BRCA2 c.9076C>G (p.Gln3026Glu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250082 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9076C>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome or other types cancer (e.g. Kauff_2002, Cheng_2017, Huang_2018, Kim_2019, Fanale_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Casadei_2019, Hart_2019). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS n=3, likely benign/benign n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

BRCA2-related cancer predisposition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Aug 06, 2024

This missense variant replaces glutamine with glutamic acid at codon 3026 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). A functional study reported that this variant has no impact on homology-directed DNA repair (PMID: 29884841). This variant has been detected in at least four individuals affected with breast or ovarian cancer (PMID: 12161607, 31161121, 33471991, 34178674; Leiden Open Variation Database DB-ID BRCA2_000398), an individual affected with skin cancer (PMID: 29625052) and a family suspected of being affected with hereditary breast and ovarian cancer (PMID: 27376475). This variant has been identified in 2/250082 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. -

BRCA2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 08, 2024

The BRCA2 c.9076C>G variant is predicted to result in the amino acid substitution p.Gln3026Glu. This variant was reported as a variant of uncertain significance in an individual with skin cancer (Supplementary Table S2B, Huang et al. 2018. PubMed ID: 29625052) and in individuals with breast and ovarian cancer (Table 3, Fanale et al. 2021. PubMed ID: 34178674). Functional studies have shown that this alteration does not affect BRCA2 function (Supplementary Table 2, Hart et al. 2018. PubMed ID: 29884841, Supplementary Table 2, Hu et al. 2022. PubMed ID: 35736817). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/52742/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Uncertain	-0.062	T
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.73	N;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0080	D;D
Vest4		0.59
MutPred		0.36		Loss of MoRF binding (P = 0.0266);Loss of MoRF binding (P = 0.0266);
MVP		0.94
MPC		0.12
ClinPred		0.90	D
GERP RS		5.7
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs80359159; hg19: chr13-32954009;