rs80358950

chr13-32355085-A-Cchr13-32355085-A-Gchr13-32355085-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP6_Very_Strong

The NM_000059.4(BRCA2):c.7232A>C(p.Lys2411Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,613,874 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (1 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:17
• Conservation: PhyloP100: 6.34

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 16 uncertain in NM_000059.4
• BP6: Variant 13-32355085-A-C is Benign according to our data. Variant chr13-32355085-A-C is described in ClinVar as [Benign]. Clinvar id is 52294.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32355085-A-C is described in Lovd as [Likely_benign]. Variant chr13-32355085-A-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.7232A>C	p.Lys2411Thr	missense_variant	14/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.7232A>C	p.Lys2411Thr	missense_variant	14/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152230 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251296 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135808

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: 0.0000440

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.0000294 AC: 43 AN: 1461644 Hom.: 1 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 727146

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74380

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000315 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:17

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:5

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Aug 13, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	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 = 0.00026 -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 03, 2022	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 18, 2022	Variant summary: BRCA2 c.7232A>C (p.Lys2411Thr) 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 6e-05 in 251296 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (6e-05 vs 0.00075), allowing no conclusion about variant significance. c.7232A>C has been reported in the literature in individuals undergoing testing for breast cancer (example, Borg_2010, Capanu_2011, Laitman_2012, van der Hout_2006). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multifactorial probability studies have reported a neutral impact (example, Easton_2007, Lindor_2012). At-least two co-occurrences with another pathogenic variant(s) have been reported in the UMD and BIC databases (BRCA1 c.5145del, p.Tyr1716fs), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating an impact on protein function (example, Guidugli_2012, Ikegami_2020). These results showed no damaging effect of this variant on homology directed repair (HDR) activity. Multiple clinical diagnostic laboratories and an expett panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Lys2411Thr variant was identified in 2 of 6116 proband chromosomes (frequency: 0.000327) from individuals or families with hereditary breast and ovarian cancer (Borg_2010, Capanu_2011, Laitman_2011) and in 1 of 2796 control chromosomes (freq. 0.00036). The variant was also identified in the following databases: dbSNP (ID: rs80358950) as “With other allele”, ClinVar (as benign by Ambry Genetics and VKGL Data-share Consensus, as likely benign by Counsyl, GeneDx, Quest Diagnostics, Color Genomics, Integrated Genetics, and Invitae, and as uncertain significance by COGR), Clinvitae (4x), LOVD 3.0 (6x), UMD-LSDB (4x as uncertain significance), and ARUP Laboratories (as not pathogenic). The variant was not identified in Cosmic, MutDB, BIC Database, or Zhejiang Colon Cancer Database. The variant was also identified by our laboratory in 1 individual with breast cancer. The variant was identified in control databases in 13 of 246082 chromosomes at a frequency of 0.000053 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 9 of 5480 chromosomes (freq: 0.001642), and European (Non-Finnish) in 4 of 111574 chromosomes (freq: 0.000036); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. One functional study demonstrated homology-directed repair activity of the variant at a level similar to nonpathogenic variants (Guidugli_2014), and four studies using a multifactorial likelihood-ratio model predict the p.Lys2411Thr variant to be neutral (Easton_2007, Guidugli_2013, Lindor_2012, Pruss_2014_25085752). The p.Lys2411 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. 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. 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	GeneDx	Aug 17, 2020	This variant is associated with the following publications: (PMID: 21990134, 26566278, 21741379, 17924331, 20104584, 20960228, 26689913, 16683254, 24323938, 25085752, 25348012, 23108138, 29036293, 32444794) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	BRCA2: BS1 -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 10, 2017	- -
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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 02, 2022	- -

BRCA2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 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). -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.070
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Uncertain	0.53	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0050	D;D
Vest4		0.45
MutPred		0.32		Loss of methylation at K2411 (P = 8e-04);Loss of methylation at K2411 (P = 8e-04);
MVP		0.97
MPC		0.17
ClinPred		0.33	T
GERP RS		5.5
gMVP		0.56

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: rs80358950; hg19: chr13-32929222;