chr2-47410109-C-G
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_001406654.1(MSH2):c.-39C>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000149 in 1,613,672 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001406654.1 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152190Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000287 AC: 72AN: 251092Hom.: 0 AF XY: 0.000391 AC XY: 53AN XY: 135698
GnomAD4 exome AF: 0.000155 AC: 226AN: 1461364Hom.: 2 Cov.: 31 AF XY: 0.000219 AC XY: 159AN XY: 726926
GnomAD4 genome AF: 0.0000919 AC: 14AN: 152308Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9AN XY: 74476
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:2
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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. -
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not provided Uncertain:1Benign:2
This variant is associated with the following publications: (PMID: 27449771, 23047549, 23729658, 25479140) -
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not specified Uncertain:1Benign:1
Variant summary: MSH2 c.382C>G (p.Leu128Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 121402 control chromosomes, predominantly at a frequency of 0.0018 within the South Asian subpopulation in the ExAC database. The observed variant frequency within South Asian control individuals in the ExAC database is approximately 3.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.382C>G has been reported in the literature in individuals affected with a variety of cancers such as ovarian, pancreatic, breast, prostate (example, Pal_2012, Grant_2015, Amemiya_2015, Yang_2016). In one family with this variant, 1 transmission of the variant allele and 1 transmission of the reference allele to affected individuals was reported (Juhari_2018). These data suggest the variant of interest does not co-segregate with the disease. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.9097dupA, p.Thr3033fsX11), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and conflicting assessments (VUS, n=5, likely benign, n=5). Based on the evidence outlined above, the variant was classified as likely benign. -
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Lynch syndrome 1 Uncertain:1
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Breast and/or ovarian cancer Benign:1
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Hereditary nonpolyposis colorectal neoplasms Benign:1
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Hereditary cancer Benign:1
This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -
Endometrial carcinoma Benign:1
The MSH2, p.Leu128Val variant was not identified in the literature. The p.Leu128Val variant was identified in dbSNP (ID: rs145649774) as “With Uncertain significance allele”, Clinvitae database (classified as VUS), MUTDB, ClinVar database (classified as uncertain significance, submitters: GeneDx, Ambry Genetics, Invitae), and UMD (1x with an “unclassified variant” classification).The p.Leu128Val variant was also identified in the NHLBI GO Exome Sequencing Project in 3 of 8600 European American alleles and 1 of 4406 African American alleles, and in the Exome Aggregation Consortium database (March 14, 2016) in 30 of 16512 chromosomes (frequency: 0.002) of South Asian individuals, 9 of 66732 (frequency: 0.00013) of European (Non-Finnish) individuals, 1 of 10404 (frequency: 9.61E-05) of African individuals, 1 of 11578 (frequency: 8.64E-05) of Latino individuals and 2 of 908 (frequency: 0.002) in other individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Leu128 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The p.Leu128Val variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The observation of this variant with a co-occurring pathogenic variant (MLH1, EXON05-8, c.381-?_677del+?) by our laboratory increases the likelihood this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time but we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Lynch syndrome Other:1
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at