chr13-32379479-C-T

Position:

• chr13-32379479-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000059.4(BRCA2):​c.8917C>T​(p.Arg2973Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,612,936 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2973H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:16
• Conservation: PhyloP100: 2.48

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 Benign. Variant got -8 ACMG points.

• BP6: Variant 13-32379479-C-T is Benign according to our data. Variant chr13-32379479-C-T is described in ClinVar as [Benign]. Clinvar id is 38193.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379479-C-T is described in Lovd as [Benign]. Variant chr13-32379479-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8917C>T	p.Arg2973Cys	missense_variant	22/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8917C>T	p.Arg2973Cys	missense_variant	22/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8548C>T	p.Arg2850Cys	missense_variant	22/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*975C>T		non_coding_transcript_exon_variant	21/26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*975C>T		3_prime_UTR_variant	21/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151970 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000241 AC: 6 AN: 249368 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134880

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: 0.0000534

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000110 AC: 161 AN: 1460966 Hom.: 0 Cov.: 31 AF XY: 0.000106 AC XY: 77 AN XY: 726750

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000132

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151970 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74208

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000773 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:16

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 17, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 19, 2021	Variant summary: BRCA2 c.8917C>T (p.Arg2973Cys) 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 249368 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8917C>T has been reported in the literature in individuals affected with breast cancer and/or ovarian cancer (Lee_2008, Spearman_2008, Lu_2012, Grant_2015, Ricks-Santi_2017, Solodskikh_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one co-occurrence with another pathogenic variant has been internally reported (BRCA1 c.68_69delAG, p.Glu23fsX17), providing supporting evidence for a benign role. Some functional studies report this variant had no or slight impact on protein function (Farrugia_2008, Guidugli_2017, Mesman_2018). Nine ClinVar submitters (evaluation after 2014) cite the variant as benign (7x) and likely benign (2x). In addition, multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be neutral (Easton_2007, Lindor_2012). Based on the evidence outlined above, the variant was classified as benign. -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:3

Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Nov 25, 2009	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	May 01, 2014	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00000178 -

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 15, 2017	- -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Arg2973Cys variant was identified in 5 of 3808 proband chromosomes (frequency: 0.001) from individuals or families with breast or pancreatic cancer and was present in 1 of 1144 control chromosomes (frequency: 0.0009) from healthy individuals (Lee 2008, Spearman 2008, Grant 2015, Ricks-Santi 2017). The variant was identified in dbSNP (rs45469092) as “with uncertain significance allele”, ClinVar (classified as benign by Ambry Genetics, GeneDx, ENIGMA, Color and 3 other submitters; as likely benign by Invitae, Counsyl, Prevention Genetics and 2 other submitters; and as uncertain significance by BIC and NIH), LOVD 3.0 (observed 10x) and UMD-LSDB (observed 1x). The variant was identified in control databases in 7 of 280,740 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 7162 chromosomes (freq: 0.0001) and European in 6 of 127,866 chromosomes (freq: 0.00005); it was not observed in the African, Latino , Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. In vitro expression of the variant demonstrated no effect on homology directed repair activity or induction of centrosome amplification (Farrugia 2008, Guidugli 2013). The variant was reported in ClinVar by another clinical laboratory to have been identified in an individual with a co-occurring pathogenic BRCA1 variant (p.Glu23fs*17), decreasing the likelihood that this variant has clinical significance (Integrated Genetics/Laboratory Corporation of America ClinVar submission dated May 31, 2018). The p.Arg2973 residue is 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. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	BRCA2: BS3:Supporting -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 25, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 26, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2014	This alteration is classified as 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. -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Feb 11, 2022

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Benign	0.72	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Uncertain	0.20	D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.62
Sift	Benign	0.046	D;D
Sift4G	Uncertain	0.055	T;T
Vest4		0.26
MVP		0.93
MPC		0.18
ClinPred		0.52	D
GERP RS		4.6
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45469092; hg19: chr13-32953616; COSMIC: COSV66451131; COSMIC: COSV66451131;