ClinVar Genomic variation as it relates to human health

In the published literature, it has been reported in multiple individuals with Familial Medullary Thyroid Cancer (FMTC) or MEN 2A (PMID: 9506724 (1998), 12409662 (2002), 18062802 (2008), 18248648 (2008), 21688339 (2012), 23756355 (2013), 26254625 (2016)). This variant is described by the American Thyroid Association (ATA) as associated with moderate risk of aggressive MTC (PMID: 25810047 (2015)). Based on the available information, the variant is classified as pathogenic.

RET: PP1:Strong, PS1, PM1, PM2, PS4:Moderate

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9506724, 26868437, 29175871, 21810974, 23756355, 22403753, 12193298, 12409662, 18062802, 12490841, 21688339, 9167962, 22965292, 26254625, 24699901, 27379493, 21626080, 26678667, 27809725, 28018431, 28609830, 28698976, 29378779, 29341155, 29590403, 30355600, 30877234, 31510104, 30787465, 31447099, 15455293, 34426522, 33087929, 14633923)

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 790 of the RET protein (p.Leu790Phe). This variant is present in population databases (rs75030001, gnomAD 0.007%). This missense change has been observed in individual(s) with medullary thyroid carcinoma and/or pheochromocytoma (PMID: 9506724, 12409662, 12490841, 21688339, 22403753, 22965292, 23756355). Notably, the p.Leu790Phe variant is associated with a less aggressive form of multiple endocrine neoplasia type 2, with fewer cases of pheochromocytoma compared to other pathogenic RET variants (PMID: 23756355, 21688339, 12490841). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 38612). 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. Experimental studies have shown that this missense change does not substantially affect RET function (PMID: 21810974). For these reasons, this variant has been classified as Pathogenic.

The c.2370G>C (p.Leu790Phe) variant has been reported in patients with familial and sporadic medullary thyroid cancer [PMID 9506724, 22965292, 21810974] and pheochromocytoma [PMID 22403753]. Segregation of the variant with medullary thyroid carcinoma was reported in several families [PMID 9506724, 22965292]. Another variant affecting the same amino acid at position 790 (c.2370G>T) and leading to the same amino acid change (p.Leu790Phe) has also been reported in patients with sporadic medullary thyroid cancer and pheochromocytoma [PMID 9506724]. A retrospective study showed that patients carrier for this p.Leu790Phe change have a non-aggressive form or slow evolving multiple endocrine neoplasia type 2 [PMID 23756355]. The role of prophylactic thyroidectomy in patients carriers for this p.Leu790Phe variant was also evaluated [PMID 21688339]. Two carriers from this study were over 70 years of age and were asymptomatic. Thus, the authors concluded that, for carriers of this p.Leu790Phe variant, a case-by-case decision instead of systematic prophylactic thyroidectomy should be discussed [PMID 21688339]. This variant was observed in two individuals at the heterozygous state in the ExAC population database (http://exac.broadinstitute.org/variant/10-43613906-G-T).This variant is highly conserved in mammals and while not clinically validated, computer-based algorithms predict this p.Leu790Phe change to be deleterious. This variant is thus classified as pathogenic. This variant is also considered medically actionable [ACMG 59, PMID 27854360].

We found this variant in a 67-year-old female with Medullary thyroid carcinoma.

Variant summary: RET c.2370G>T (p.Leu790Phe) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251550 control chromosomes (gnomAD and Berndt_1998). c.2370G>T has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2A/Familial Medullary Thyroid Cancer and has been found to segregate with disease within families (e.g. Berndt_1998, Gimm_2002, Romei_2010, Bihan_2011). These data indicate that the variant is very likely to be associated with disease. Another variant resulting in the same amino acid change, c.2370G>C (p.Leu790Phe) has also been reported in affected individuals (e.g. Gimm_2002), providing additional evidence supporting a pathogenic role. The following publications have been ascertained in the context of this evaluation (PMID: 9506724, 20516206, 21688339, 12490841). Multiple submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and the majority have classified the variant as pathogenic (n=13), with one submitter classifying it as VUS. Based on the evidence outlined above, the variant was classified as pathogenic.

PP1_strong, PP4, PP5, PM2, PS4_moderate

This missense variant replaces leucine with phenylalanine at codon 790 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has reported that this variant protein does not confer significant cell transforming activity in transfected ex vivo cells (PMID: 21810974). This variant has been reported in multiple individuals affected with medullary thyroid cancer (PMID: 9506724, 12409662, 12490841, 18062802, 26254625, 27379493, 32411094, 33827484) and an individual affected with bilateral adrenal pheochromocytoma (PMID: 22403753). This variant is also reported to segregate with medullary thyroid cancer in individuals from over 10 families (PMID: 9506724, 12409662, 33827484). This variant has been described as a low- to moderate-risk variant for medullary thyroid cancer based on the American Thyroid Association stratification (PMID: 23756355, 33167350, 33827484). This variant has been identified in 5/251150 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

The RET c.2370G>T, p.Leu790Phe variant (rs75030001) has been reported in multiple individuals with medullary thyroid carcinoma (MTC), segregates with disease in families with MTC, and has also been described in individuals with pheochromocytoma (Berndt 1998, Bihan 2011, Bihan 2013, Fitze 2002, Fussey 2021, Min 2012). This variant is listed as pathogenic in ClinVar (Variation ID: 38612) and is observed in the general population at a low overall frequency of 0.002% (5/251,150 alleles) in the Genome Aggregation Database. The leucine at codon 790 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.733). Additionally, another variant that results in the same amino acid change (c.2370G>C; p.Leu790Phe) has been reported in individuals affected with MTC (Berndt 1998). Based on available information, the c.2370G>T variant is considered pathogenic. References: Berndt I et al. A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. 1998;J Clin Endocrinol Metab. 83(3):770-4. PMID: 9506724 Bihan H et al. Role of prophylactic thyroidectomy in RET 790 familial medullary thyroid carcinoma. Head Neck. 2012 Apr;34(4):493-8. PMID: 21688339. Bihan H et al. The clinical spectrum of RET proto-oncogene mutations in codon 790. 2013;Eur J Endocrinol. 169(3):271-6. PMID: 23756355. Fitze G et al. Various penetrance of familial medullary thyroid carcinoma in patients with RET protooncogene codon 790/791 germline mutations. Ann Surg. 2002 Nov;236(5):570-5. PMID: 12409662. Fussey JM et al. Diagnostic RET genetic testing in 1,058 index patients: A UK centre perspective. Clin Endocrinol (Oxf). 2021 Aug;95(2):295-302. PMID: 33340421. Min J et al. Bilateral adrenal pheochromocytoma with a germline L790F mutation in the RET oncogene. J Korean Surg Soc. 2012 Mar;82(3):185-9. PMID: 22403753.

The c.2370G>C (p.Leu790Phe) variant has been reported in patients with familial and sporadic medullary thyroid cancer [PMID 9506724, 22965292, 21810974] and pheochromocytoma [PMID 22403753]. Segregation of the variant with medullary thyroid carcinoma was reported in several families [PMID 9506724, 22965292]. Another variant affecting the same amino acid at position 790 (c.2370G>T) and leading to the same amino acid change (p.Leu790Phe) has also been reported in patients with sporadic medullary thyroid cancer and pheochromocytoma [PMID 9506724]. A retrospective study showed that patients carrier for this p.Leu790Phe change have a non-aggressive form or slow evolving multiple endocrine neoplasia type 2 [PMID 23756355]. The role of prophylactic thyroidectomy in patients carriers for this p.Leu790Phe variant was also evaluated [PMID 21688339]. Two carriers from this study were over 70 years of age and were asymptomatic. Thus, the authors concluded that, for carriers of this p.Leu790Phe variant, a case-by-case decision instead of systematic prophylactic thyroidectomy should be discussed [PMID 21688339]. This variant was observed in two individuals at the heterozygous state in the ExAC population database (http://exac.broadinstitute.org/variant/10-43613906-G-T).This variant is highly conserved in mammals and while not clinically validated, computer-based algorithms predict this p.Leu790Phe change to be deleterious. This variant is thus classified as pathogenic. This variant is also considered medically actionable [ACMG 59, PMID 27854360].

This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 33827484, 33167350, 12490841, 12409662, 9506724, 25810047].

The p.L790F pathogenic mutation (also known as c.2370G>T), located in coding exon 13 of the RET gene, results from a G to T substitution at nucleotide position 2370. The leucine at codon 790 is replaced by phenylalanine, an amino acid with highly similar properties. This mutation has been described in a German family with multiple endocrine neoplasia type 2 (MEN2); the index case and three other affected family members all had medullary thyroid cancer (MTC) and a pheochromocytoma (PCC) and two other affected family members had medullary thyroid cancer only. This mutation was not detected in 200 controls (Berndt I et al. J. Clin. Endocrinol. Metab. 1998 Mar;83:770-4). Subsequently, this mutation has been observed in patients with MTC and/or PCC of various ethnic backgrounds, including French, Korean, and Chinese (Min JW et al. J Korean Surg Soc. 2012 Mar;82:185-9; Bihan H et al. Head Neck. 2012 Apr;34:493-8; Qi XP et al. Thyroid. 2012 Dec;22:1257-65; Pirich C et al. Wien. Klin. Wochenschr. 2012 Oct;124:723-4; Innella G et al. Cancers (Basel). 2020 Nov;12:). Family members of two unrelated cases of MTC who underwent presymptomatic testing for this mutation and tested positive elected to undergo prophylactic thyroidectomy and were found to have c-cell hyperplasia at age 9 and age 16 (Fitze G et al. Ann. Surg. 2002 Nov;236:570-5). The American Thyroid Association has designated alterations at this codon occurring without additional RET mutations as moderate risk mutations (Wells SA et al. Thyroid. 2015 Jun;25:567-610). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is pathogenic with moderate risk for MEN2; however, the association of this alteration with Hirschsprung disease is unknown.

The p.Leu790Phe variant in the RET gene has been previously reported in at least 50 individuals with medullary thyroid cancer (Berndt et al., 1998; Brauckhoff et al., 2002; Gimm et al., 2002; Bihan et al., 2012; Larsen et al., 2020), as well as in individuals with pheochromocytoma (Berndt et al., 1998; Min et al., 2012), and segregated with disease in several families (Berndt et al., 1998; Bihan et al., 2012). This variant has been classified as a moderate risk allele primarily associated with the FMTC and MEN2A phenotypes (Loveday et al., 2018). This variant has been identified in 5/251,150 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Additionally, a different nucleotide change (c.2370G>C) resulting in an identical amino change has been previously reported. The c.2370G>C (p.Leu790Phe) variant is pathogenic and is expected to result in a similar disruption to protein function as c.2370G>T. Computational tools predict that p.Leu790Phe is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Leu790Phe variant as pathogenic for autosomal dominant multiple endocrine neoplasia type 2 based on the information above. [ACMG evidence codes used: PS1; PS4; PM2; PP3]

Variant interpreted as Pathogenic and reported on 11-04-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.