Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000205972 | SCV000261889 | uncertain significance | Familial adenomatous polyposis 2 | 2023-12-14 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 420 of the MUTYH protein (p.Leu420Val). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 28202063). ClinVar contains an entry for this variant (Variation ID: 220923). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Counsyl | RCV000205972 | SCV000487367 | uncertain significance | Familial adenomatous polyposis 2 | 2016-06-23 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000563480 | SCV000662597 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-03-26 | criteria provided, single submitter | clinical testing | The p.L420V variant (also known as c.1258C>G), located in coding exon 13 of the MUTYH gene, results from a C to G substitution at nucleotide position 1258. The leucine at codon 420 is replaced by valine, an amino acid with highly similar properties. This alteration was detected in a cohort of 45 Lebanese breast cancer patients undergoing whole exome sequencing (Jalkh N et al. BMC Med Genomics, 2017 02;10:8). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Color Diagnostics, |
RCV000563480 | SCV000685558 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-06-20 | criteria provided, single submitter | clinical testing | This missense variant replaces leucine with valine at codon 420 of the MUTYH protein. This variant is also known as c.1216C>G (p.Leu406Val) based on an alternative transcript (NM_001048171). 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 28202063; Sas 2015). This variant has also been identified in 1/251166 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. |
| Mendelics | RCV000205972 | SCV000837749 | uncertain significance | Familial adenomatous polyposis 2 | 2018-07-02 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001201302 | SCV001372439 | uncertain significance | not specified | 2020-06-16 | criteria provided, single submitter | clinical testing | Variant summary: MUTYH c.1258C>G (p.Leu420Val) results in a conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) / MutY, C-terminal (IPR029119) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251166 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1258C>G has been reported in the literature in individuals affected with breast cancer (Jalkh_2017). This report, however does not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |