rs587780138

Variant names:

• chr11-94490959-ATCATCACTATAT-A
• rs587780138
• NM_005591.4:c.21-6_26delATATAGTGATGA

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_005591.4(MRE11):​c.21-6_26delATATAGTGATGA​(p.Asp8_Asp9del) variant causes a splice acceptor, conservative inframe deletion, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000286 in 1,293,142 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: MRE11 NM_005591.4 splice_acceptor, conservative_inframe_deletion, splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.28
• Publications: 1 publications found

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]

MRE11 Gene-Disease associations (from GenCC):

• ataxia-telangiectasia-like disorder 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• prostate cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 11-94490959-ATCATCACTATAT-A is Pathogenic according to our data. Variant chr11-94490959-ATCATCACTATAT-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127979.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRE11	NM_005591.4	c.21-6_26delATATAGTGATGA	p.Asp8_Asp9del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 3 of 20	ENST00000323929.8	NP_005582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8	c.21-6_26delATATAGTGATGA	p.Asp8_Asp9del	splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant	Exon 3 of 20	1	NM_005591.4	ENSP00000325863.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000124 AC: 3 AN: 242138 AF XY: 0.0000152

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000276

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000286 AC: 37 AN: 1293142 Hom.: 0 AF XY: 0.0000292 AC XY: 19 AN XY: 651572

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29950

American (AMR) AF: 0.00 AC: 0 AN: 44174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25046

East Asian (EAS) AF: 0.00 AC: 0 AN: 38688

South Asian (SAS) AF: 0.00 AC: 0 AN: 82422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4834

European-Non Finnish (NFE) AF: 0.0000374 AC: 36 AN: 961546

Other (OTH) AF: 0.0000183 AC: 1 AN: 54648

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000151246), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 29, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.21-6_26del12 variant, which spans part of coding exon 2 of the MRE11A gene, results from a deletion of 12 nucleotides between positions 21-6 and 26, and removes the canonical splice acceptor sequence at c.21-2_-1. This alteration has been previously reported as a splicing mutation detected in a breast/ovarian cancer family (Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011;108:18032-7). In addition, c.21-6_26del12 was reported in an individual with colorectal cancer diagnosed under age 55 with at least one first degree relative with colorectal cancer (Chubb D et al. Nat Commun 2016 Jun;7:11883). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

Ataxia-telangiectasia-like disorder 1 Pathogenic:1

Mar 23, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia-like disorder Pathogenic:1

May 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant results in the deletion of part of exon 3 (c.21-6_26del) of the MRE11 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MRE11 are known to be pathogenic (PMID: 23080121, 23912341). This variant is present in population databases (rs587780138, gnomAD 0.003%). This variant has been observed in individual(s) with ovarian and colorectal cancer (PMID: 22006311, 27329137). ClinVar contains an entry for this variant (Variation ID: 127979). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587780138; hg19: chr11-94224125;