ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1941C>T (p.Ile647=) (rs75225191)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001085461 SCV000261587 likely benign Multiple endocrine neoplasia, type 2 2019-12-31 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 Synonymous alterations with insufficient evidence to classify as benign
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
OMIM RCV000014966 SCV000035222 risk factor Hirschsprung disease 1 1999-04-01 no assertion criteria provided literature only

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