2-47470955-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000251.3(MSH2):c.1662-10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000746 in 1,326,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 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_000251.3 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000724 AC: 11AN: 152036Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249748Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135228
GnomAD4 exome AF: 0.0000741 AC: 87AN: 1174736Hom.: 0 Cov.: 18 AF XY: 0.0000718 AC XY: 43AN XY: 598868
GnomAD4 genome AF: 0.0000789 AC: 12AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74382
ClinVar
Submissions by phenotype
not provided Benign:2
The MSH2 c.1662-10C>T variant was not identified in the literature nor was it identified in the UMD-LSDB, database. The variant was identified in dbSNP (ID: rs752606387) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae and Color Genomics; classified as uncertain significance by Integrated Genetics/Laboratory Corporation of America). The variant was identified by our laboratory in a patient with breast cancer under the age of 30 and a co-occurring BRCA1 pathogenic variant (BRCA1, c.1100del). The variant was identified in control databases in 7 of 276086 chromosomes at a frequency of 0.000025 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 23982 chromosomes (freq: 0.00004), European Non-Finnish in 5 of 126050 chromosomes (freq: 0.00004), and South Asian in 1 of 30530 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, or European Finnish populations. The variant occurs outside of the splicing consensus sequence and 0 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The MSH2 c.1662-10C nucleotide is not conserved in mammals and a C>T substitution is observed in several species. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
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Breast and/or ovarian cancer Uncertain:1
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not specified Benign:1
Variant summary: MSH2 c.1662-10C>T alters a nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00014 in 249838 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (0.00014 vs 0.00057), allowing no conclusion about variant significance. c.1662-10C>T has been reported in the literature in individuals affected with Cancer (Davison_2012) without evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 414995). Based on the evidence outlined above, the variant was classified as likely benign. -
Hereditary nonpolyposis colorectal neoplasms Benign:1
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Hereditary cancer-predisposing syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at