rs587780138

chr11-94490959-ATCATCACTATAT-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_005591.4(MRE11):c.21-6_26del variant causes a splice acceptor, coding sequence, 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. 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, coding_sequence, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 7.28

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 Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: Splicing 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 id is 127979.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRE11	NM_005591.4	c.21-6_26del		splice_acceptor_variant, coding_sequence_variant, intron_variant	3/20	ENST00000323929.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRE11	ENST00000323929.8	c.21-6_26del		splice_acceptor_variant, coding_sequence_variant, intron_variant	3/20	1	NM_005591.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000124 AC: 3 AN: 242138 Hom.: 0 AF XY: 0.0000152 AC XY: 2 AN XY: 131214

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: 0.0000276

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

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000374

Gnomad4 OTH exome AF: 0.0000183

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia-telangiectasia-like disorder 1 Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 07, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 05, 2019	The MRE11A c.21-6_26delATATAGTGATGA variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.21-6_26delATATAGTGATGA variant has not been reported in the literature in association with ataxia-telangiectasia-like disorder. It has, however, been reported in at least two studies in which it is found in a heterozygous state in two individuals, including in one individual with stage 3c/grade 3 serous ovarian cancer and a personal and family history of breast cancer who carried a truncating variant in BRCA2, and in one individual with early-onset colorectal cancer who did not meet Amsterdam II criteria despite a first-degree relative with colorectal cancer (Walsh et al. 2011; Chubb et al. 2016). The c.21-6_26delATATAGTGATGA variant was absent from 5,226 controls but is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Genome Aggregation Database. Using RT-PCR, analysis of mRNA from the individual with ovarian cancer suggests that this variant alters splicing and results in a frameshift and early termination of the coding sequence (Walsh et al. 2011). Due to the potential impact of splice acceptor variants and limited evidence, the c.21-6_26delATATAGTGATGA variant is classified as a variant of unknown significance but suspicious for pathogenicity for ataxia-telangiectasia-like disorder. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 17, 2022	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). Based on two different splice site prediction tools, this alteration is expected to abolish the native splice acceptor site; however, experimental evidence is not available. 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 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 11, 2023

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 127979). This variant has been observed in individual(s) with ovarian and colorectal cancer (PMID: 22006311, 27329137). This variant is present in population databases (rs587780138, gnomAD 0.003%). 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). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587780138; hg19: chr11-94224125;