chr13-32394707-A-G

Position:

• chr13-32394707-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3 BP6

The NM_000059.4(BRCA2):​c.9275A>G​(p.Tyr3092Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000657 in 1,613,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:14
• Conservation: PhyloP100: 6.06

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.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838
• BP6: Variant 13-32394707-A-G is Benign according to our data. Variant chr13-32394707-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52800.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Uncertain_significance=2, Benign=1}. Variant chr13-32394707-A-G is described in Lovd as [Likely_benign]. Variant chr13-32394707-A-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9275A>G	p.Tyr3092Cys	missense_variant	25/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9275A>G	p.Tyr3092Cys	missense_variant	25/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8906A>G	p.Tyr2969Cys	missense_variant	25/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1333A>G		non_coding_transcript_exon_variant	24/26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*1333A>G		3_prime_UTR_variant	24/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000758 AC: 19 AN: 250616 Hom.: 0 AF XY: 0.0000812 AC XY: 11 AN XY: 135460

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000671 AC: 98 AN: 1461250 Hom.: 0 Cov.: 31 AF XY: 0.0000729 AC XY: 53 AN XY: 726902

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74262

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000656 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Jan 15, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jun 14, 2012	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	 The BRCA2 p.Tyr3092Cys variant was identified in 3 of 7064 proband chromosomes (frequency: 0.0004) from Portugese, French and American individuals or families with (hereditary) breast and ovarian cancer (Peixoto 2015, Lee 2008 , Malone 2000, Caux-Moncoutier 2011). Functional assays looking at allelic imbalance, homologous directed DNA repair (HDR) and splicing of the variant did not show any defects and the variant was classified as likely not pathogenic (Caux-Moncoutier 2009, Guidugli 2013, Houdayer 2012). In silico models (protein likelihood ratio and multifactorial probability) also classify the variant as neutral/likely benign (Karchin 2008, Lindor 2012, Easton 2007). The variant is reported in ClinVar (Conflicting interpretations of pathogenicity. Benign by Mendelics in 2019. Likely benign by Counsyl in 2015, Integrated Genetics in 2017, GeneDx in 2017, Invitae in 2019, ARUP Laboratories in 2019, Quest Diagnostics in 2019, Ambry in 2018, Color in 2016, SCRP in 2012, Foulkes Cancer Genetics LDI in 2010. Uncertain significance by BIC in 2004, Erasmus Medical Unit in 2015, PLM at Sinai Health System in 2015, Genome Diagnostics Laboratory at Utrecht Universitiy Medical Cenre in 2014, Soonchunhyang University Bucheon Hospital in 2016), LOVD 2.0 (20 entries, 16x VUS, 1x LB, 1x B), ARUP laboratories (2 - Likely not pathogenic or of little clinical significance) databases. The variant was identified in dbSNP (rs80359195) as Uncertain significance. The variant was identified by our laboratory in 1 individual with breast cancer. The variant was identified in control databases in 20 of 281996 chromosomes at a frequency of 0.00007092 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 5 of 30528 chromosomes (freq: 0.000164), Latino in 5 of 35332 chromosomes (freq: 0.000142), Other in 1 of 7194 chromosomes (freq: 0.000139), European (non-Finnish) in 8 of 128648 chromosomes (freq: 0.000062), East Asian in 1 of 19938 chromosomes (freq: 0.00005), but was not observed in the African, Ashkenazi Jewish, or European (Finnish) populations. UMD reports the variant to co-occur with a pathogenic BRCA2 variant, c.6275_6276delTT (p.Leu2092ProfsX7) (from Integrated Genetics ClinVar blurb, SCV000695231.1). The p.Tyr3092 residue is conserved in mammals and more distantly related organisms, and 8 out of 8 computational predictors (MUT Assesor, SIFT, Polyphen2, MT, FATHMM, DANN, MetaLR, Revel) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, the clinical significance of this variant cannot be determined at this time, though we would lean toward a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2021	This variant is associated with the following publications: (PMID: 31131967, 32438681, 17924331, 21990134, 19043619, 22505045, 25782689, 10717622, 23108138, 19471317, 21120943, 24916970, 29394989, 18284688, 30040829, 25348012, 12427538, 29625052, 29884841, 32806537) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 31, 2023	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 06, 2022	Variant summary: BRCA2 c.9275A>G (p.Tyr3092Cys) results in a non-conservative amino acid change located in the OB3 domain (IPR015188) of 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 8e-05 in 250758 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (8e-05 vs 0.00075), allowing no conclusion about variant significance. c.9275A>G has been reported in the literature in individuals suspected of or affected with Hereditary Breast And Ovarian Cancer Syndrome, without strong evidence for causality (e.g. Lee_2008, Caux-Moncoutier_2009, Juwle_2012, Peixoto_2014, Kowalik_2018, Santonocito_2020, Park_2021). Therefore, 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 in the UMD database (BRCA2 c.6275_6276delTT, p.Leu2092ProfsX7), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function. These studies found that the variant has no impact on splicing and has normal HDR activity (e.g. Caux-Moncoutier_2009, Houdayer_2012, Guidugli_2012). Eleven submitters have provided assessments for this variant to ClinVar after 2014. The majority classified the variant as either benign (n=1) or likely benign (n=8) and two classified the variant as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 10, 2019	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 16, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 05, 2018	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. -

Hereditary breast ovarian cancer syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -

Breast and/or ovarian cancer Benign:1

Likely benign, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Apr 21, 2010

- -

BRCA2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 15, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.76	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.95
MVP		0.96
MPC		0.18
ClinPred		0.34	T
GERP RS		5.9
gMVP		0.71

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: rs80359195; hg19: chr13-32968844; COSMIC: COSV99061634; COSMIC: COSV99061634;