NM_005591.4(MRE11):c.1475C>A (p.Ala492Asp) AND Ataxia-telangiectasia-like disorder 1

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Oct 14, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000524517.25

Allele description [Variation Report for NM_005591.4(MRE11):c.1475C>A (p.Ala492Asp)]

NM_005591.4(MRE11):c.1475C>A (p.Ala492Asp)

Gene:

MRE11:MRE11 homolog, double strand break repair nuclease [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q21

Genomic location:

Preferred name:

NM_005591.4(MRE11):c.1475C>A (p.Ala492Asp)

Other names:

p.A492D:GCC>GAC; NP_005582.1:p.Ala492Asp

HGVS:

NC_000011.10:g.94459433G>T
NG_007261.1:g.39442C>A
NM_001330347.2:c.1475C>A
NM_005590.4:c.1475C>A
NM_005591.4:c.1475C>AMANE SELECT
NP_001317276.1:p.Ala492Asp
NP_005581.2:p.Ala492Asp
NP_005582.1:p.Ala492Asp
NP_005582.1:p.Ala492Asp
LRG_85t1:c.1475C>A
LRG_85:g.39442C>A
LRG_85p1:p.Ala492Asp
NC_000011.8:g.93832247G>T
NC_000011.9:g.94192599G>T
NM_001330347.1:c.1475C>A
NM_005591.3:c.1475C>A
p.A492D

Protein change:

A492D

Links:

dbSNP: rs61749249

NCBI 1000 Genomes Browser:

rs61749249

Molecular consequence:

NM_001330347.2:c.1475C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005590.4:c.1475C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005591.4:c.1475C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Ataxia-telangiectasia-like disorder 1 (ATLD1)
Identifiers:: MONDO: MONDO:0024557; MedGen: C4012790; Orphanet: 251347; OMIM: 604391

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000604243	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Uncertain significance (Oct 14, 2023)	germline	clinical testing	Citation Link,
SCV000785308	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Likely benign (Jul 5, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28051113, 26898890, 26483394 Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV001271758	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Benign (Apr 27, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001483058	Baylor Genetics - CSER-TexasKidsCanSeq	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 30, 2018)	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A comprehensive custom panel design for routine hereditary cancer testing: preserving control, improving diagnostics and revealing a complex variation landscape.

Castellanos E, Gel B, Rosas I, Tornero E, Santín S, Pluvinet R, Velasco J, Sumoy L, Del Valle J, Perucho M, Blanco I, Navarro M, Brunet J, Pineda M, Feliubadaló L, Capellá G, Lázaro C, Serra E.

Sci Rep. 2017 Jan 4;7:39348. doi: 10.1038/srep39348.

PubMed [citation]

PMID:: 28051113
PMCID:: PMC5209725

Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations.

Caminsky NG, Mucaki EJ, Perri AM, Lu R, Knoll JH, Rogan PK.

Hum Mutat. 2016 Jul;37(7):640-52. doi: 10.1002/humu.22972. Epub 2016 Mar 18.

PubMed [citation]

PMID:: 26898890

See all PubMed Citations (5)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000604243.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The MRE11 c.1475C>A; p.Ala492Asp variant (rs61749249) is reported in the literature in individuals with hereditary breast and ovarian cancer syndrome, colon cancer, or pancreatic cancer (Caminsky 2016, Castellanos 2017, Hu 2016, Taghizadeh 2020). However, this variant is also found in the non-Finnish European population with an allele frequency of 0.56% (720/129116 alleles, including 3 homozygotes) in the Genome Aggregation Database. This variant is reported in the ClinVar database (Variation ID: 127031). The alanine at codon 492 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.234). Based on available information, the clinical significance of this variant is uncertain at this time. References: Caminsky NG et al. Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations. Hum Mutat. 2016 Jul;37(7):640-52. PMID: 26898890 Castellanos E et al. A comprehensive custom panel design for routine hereditary cancer testing: preserving control, improving diagnostics and revealing a complex variation landscape. Sci Rep. 2017 Jan 4;7:39348. PMID: 28051113 Hu C et al. Prevalence of Pathogenic Mutations in Cancer Predisposition Genes among Pancreatic Cancer Patients. Cancer Epidemiol Biomarkers Prev. 2016 Jan;25(1):207-11. PMID: 26483394 Taghizadeh H et al. Applied precision medicine in metastatic pancreatic ductal adenocarcinoma. Ther Adv Med Oncol. 2020 Jul 10;12:1758835920938611. PMID: 32699558;

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000785308.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001271758.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics - CSER-TexasKidsCanSeq, SCV001483058.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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