ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1941C>T (p.Ile647=)

gnomAD frequency: 0.00002  dbSNP: rs75225191
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001085461 SCV000261587 likely benign Multiple endocrine neoplasia, type 2 2024-01-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV000220871 SCV000275303 likely benign Hereditary cancer-predisposing syndrome 2018-12-31 criteria provided, single submitter clinical testing 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.
GeneDx RCV000519499 SCV000616853 uncertain significance not provided 2017-09-21 criteria provided, single submitter clinical testing This variant is denoted RET c.1941C>T at the DNA level. Although the variant is silent at the coding level, preserving an Isoleucine at codon 647, it has been demonstrated to cause abnormal splicing (Auricchio et al., 1999). It was observed in an individual with Hirschsprung disease who inherited the variant from an unaffected mother. This individual also harbored a paternally inherited variant in a different Hirschsprung-associated gene (EDNRB) (Auricchio et al., 1999). RET c.1941C>T has also been reported in two other individuals with sporadic Hirschsprung disease as well as in one familial case (Sancandi et al., 2000, Fitze et al., 2002, Pelet et al., 2005). However, this variant, has not, to our knowledge, been reported in association with multiple endocrine neoplasia type 2 (MEN2). RET c.1941C>T was observed with an allele frequency of 0.05% (9/16,508) in individuals of South Asian ancestry in the ExAC dataset (Lek et al., 2016). The nucleotide which is altered, a cytosine (C) at base 1941, is not conserved. Based on currently available evidence, it is unclear whether RET c.1941C>T is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Mendelics RCV000988344 SCV001138027 benign Multiple endocrine neoplasia type 2A 2019-05-28 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000220871 SCV002529954 likely benign Hereditary cancer-predisposing syndrome 2021-12-13 criteria provided, single submitter curation
CeGaT Center for Human Genetics Tuebingen RCV000519499 SCV004127598 likely benign not provided 2023-07-01 criteria provided, single submitter clinical testing RET: BP4, BP7
Color Diagnostics, LLC DBA Color Health RCV001085461 SCV004357236 likely benign Multiple endocrine neoplasia, type 2 2022-11-14 criteria provided, single submitter clinical testing
OMIM RCV000014966 SCV000035222 risk factor Hirschsprung disease, susceptibility to, 1 1999-04-01 no assertion criteria provided literature only

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