2-47408449-C-G
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BP6
The NM_001406656.1(MSH2):c.-736C>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000205 in 1,611,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001406656.1 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151214Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.00000399 AC: 1AN: 250910 AF XY: 0.00000737 show subpopulations
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1460314Hom.: 0 Cov.: 32 AF XY: 0.0000262 AC XY: 19AN XY: 726470 show subpopulations
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151214Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 73748 show subpopulations
ClinVar
Submissions by phenotype
Lynch syndrome 1 Uncertain:2Benign:1
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. -
- -
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
Hereditary cancer-predisposing syndrome Uncertain:2
This missense variant replaces serine with cysteine at codon 87 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (ClinGen VCEP defined LOF score threshold <=0, PMID: 33357406). This variant has been reported in individuals affected with breast, pancreatic or primary peritoneal cancers (PMID: 29659587, 29945567, 32547938). This variant has been identified in 2/282148 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
The p.S87C variant (also known as c.260C>G), located in coding exon 2 of the MSH2 gene, results from a C to G substitution at nucleotide position 260. The serine at codon 87 is replaced by cysteine, an amino acid with dissimilar properties. This alteration was identified in a cohort of pancreatic cancer patients undergoing multigene panel testing (Young EL et al. BMC Cancer, 2018 Jun;18:697) and in a woman with primary peritoneal cancer who tested negative for the BRCA1 mutation previously identified in her family (Mitchell R et al. PLoS One, 2018 Apr;13:e0195497). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Lynch syndrome Uncertain:1
This missense variant replaces serine with cysteine at codon 87 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with breast, pancreatic or primary peritoneal cancers (PMID: 29659587, 29945567, 32547938). This variant has been identified in 2/282148 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
This variant is denoted MSH2 c.260C>G at the cDNA level, p.Ser87Cys (S87C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ser87Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH2 Ser87Cys is located in the mismatch binding domain (Lutzen 2008, Kansikas 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether MSH2 Ser87Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Hereditary nonpolyposis colorectal neoplasms Benign:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at