rs104895016

chr11-94459428-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_005591.4(MRE11):c.1480G>A(p.Glu494Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000489 in 1,613,872 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (1 hom.)
• Consequence: MRE11 NM_005591.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5 O:1
• Conservation: PhyloP100: 7.84

Genes affected

MRE11 (HGNC:7230): (MRE11 homolog, double strand break repair nuclease) This gene encodes a nuclear protein involved in homologous recombination, telomere length maintenance, and DNA double-strand break repair. By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity. The protein forms a complex with the RAD50 homolog; this complex is required for nonhomologous joining of DNA ends and possesses increased single-stranded DNA endonuclease and 3' to 5' exonuclease activities. In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short homologies near the ends of the DNA fragments. This gene has a pseudogene on chromosome 3. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 11-94459428-C-T is Benign according to our data. Variant chr11-94459428-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127030.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, not_provided=1, Likely_benign=4, Benign=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000508 (742/1461648) while in subpopulation SAS AF= 0.000812 (70/86250). AF 95% confidence interval is 0.000658. There are 1 homozygotes in gnomad4_exome. There are 378 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRE11	NM_005591.4	c.1480G>A	p.Glu494Lys	missense_variant	13/20	ENST00000323929.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRE11	ENST00000323929.8	c.1480G>A	p.Glu494Lys	missense_variant	13/20	1	NM_005591.4	P3
MRE11	ENST00000323977.7	c.1480G>A	p.Glu494Lys	missense_variant	13/19	1
MRE11	ENST00000407439.7	c.1489G>A	p.Glu497Lys	missense_variant	13/20	2
MRE11	ENST00000393241.8	c.1480G>A	p.Glu494Lys	missense_variant	13/20	5		A1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000469 AC: 118 AN: 251372 Hom.: 0 AF XY: 0.000478 AC XY: 65 AN XY: 135874

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000757

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000508 AC: 742 AN: 1461648 Hom.: 1 Cov.: 31 AF XY: 0.000520 AC XY: 378 AN XY: 727132

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000812

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.000568

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74440

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000455 Hom.: 0

Bravo AF: 0.000196

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000593 AC: 72

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1 Other:1

not provided, no classification provided	literature only	Harris Lab, University of Minnesota	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 15, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer and present only in controls in a study of common variable immunodeficiency (CVID) (Offer et al., 2010; Couch et al., 2015; Caminsky et al., 2016); This variant is associated with the following publications: (PMID: 25452441, 26898890, 25344691, 20805886) -

Ataxia-telangiectasia-like disorder 1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 18, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 13, 2023	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Feb 16, 2018

Variant summary: MRE11A c.1480G>A (p.Glu494Lys) results in a conservative amino acid change located in the outside of any known domain or repeat of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency of 0.00049 (136/277134 chrs) is approximately 8.083 fold of the estimated maximal expected allele frequency for a pathogenic variant in MRE11A causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is benign. The c.1480G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

Ataxia-telangiectasia-like disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Uncertain	0.10
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.6	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.078	T;T;D;D
Sift4G	Uncertain	0.039	D;D;D;D
Polyphen		0.94	P;.;P;.
Vest4		0.86
MVP		0.80
MPC		0.19
ClinPred		0.10	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.30
gMVP		0.35

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: rs104895016; hg19: chr11-94192594; COSMIC: COSV60575336;