ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1558+5G>A (rs199935667)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115461 SCV000218331 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000115461 SCV000684754 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Counsyl RCV000663109 SCV000786227 uncertain significance Lynch syndrome II 2018-03-23 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515436 SCV000611398 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000590226 SCV000149370 uncertain significance not provided 2018-11-27 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1558+5G>A or IVS13+5G>A and consists of a G>A nucleotide substitution at the +5 position of intron 13 of the MLH1 gene. Multiple in silico models predict this variant to either damage or destroy the nearby natural splice donor site, and to possibly cause abnormal gene splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This splice variant has been previously reported in one family fulfilling Amsterdam criteria II for Lynch syndrome (Tang 2009). MLH1 c.1558+5G>A was observed at an allele frequency of 0.1% (19/18868) in individuals of East Asian ancestry in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether MLH1 c.1558+5G>A is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590226 SCV000696115 uncertain significance not provided 2017-07-06 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1558+5G>A variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict the weakening of a canonical 5' splice donor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 13/121390 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.001156 (10/8650). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105), suggesting this may be a benign polymorphism found primarily in the populations of East Asian origin. The variant has been reported in at least one affected individual in the literature without strong evidence for causality. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, with one reporting the variant to co-occur in a patient with a pathogenic mutation in a different gene, suggesting the variant is not the primary cause of disease in that patient. Taken together, this variant is classified as VUS until additional evidence becomes available.
Invitae RCV000204397 SCV000259283 likely benign Hereditary nonpolyposis colon cancer 2017-05-08 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000758646 SCV000887407 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MLH1 NM_000249.3:c.1558+5G>A has a 59.6% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.

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