ClinVar Miner

Submissions for variant NM_000077.5(CDKN2A):c.388C>A (p.Leu130Met)

dbSNP: rs1060501261
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000468731 SCV000545518 uncertain significance Familial melanoma 2024-05-31 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 130 of the CDKN2A (p16INK4a) protein (p.Leu130Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. ClinVar contains an entry for this variant (Variation ID: 406704). 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 disruptive. 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.
Ambry Genetics RCV001021362 SCV001182970 uncertain significance Hereditary cancer-predisposing syndrome 2023-10-25 criteria provided, single submitter clinical testing The p.L130M variant (also known as c.388C>A), located in coding exon 2 of the CDKN2A gene, results from a C to A substitution at nucleotide position 388. The leucine at codon 130 is replaced by methionine, an amino acid with highly similar properties. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193448 SCV001362279 uncertain significance not specified 2019-09-06 criteria provided, single submitter clinical testing Variant summary: CDKN2A c.388C>A (p.Leu130Met) results in a conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245266 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.388C>A has been reported in the literature as a somatic mutation in an individual affected with oesophageal adenocarcinoma (Findlay_2016). However, this report does not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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