Submissions for variant NM_001042492.3(NF1):c.6929C>T (p.Pro2310Leu)

gnomAD frequency: 0.00015  dbSNP: rs148736217

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129366	SCV000184130	likely benign	Hereditary cancer-predisposing syndrome	2016-01-19	criteria provided, single submitter	clinical testing	Insufficient or conflicting evidence;Other data supporting benign classification
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082296	SCV000218706	benign	Neurofibromatosis, type 1	2025-02-04	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000214790	SCV000272222	benign	not specified	2017-10-10	criteria provided, single submitter	clinical testing	p.Pro2310Leu in exon 47 of NF1: This variant is not expected to have clinical si gnificance because it has been identified in 0.5% (52/10152) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinst itute.org/; dbSNP rs148736217). ACMG/AMP Criteria applied: BA1 (Richards 2015).
GeneDx	RCV000034587	SCV000720772	benign	not provided	2019-09-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29089047, 22703879, 28873162)
Illumina Laboratory Services, Illumina	RCV001122580	SCV001281306	uncertain significance	Café-au-lait macules with pulmonary stenosis	2018-01-15	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001122581	SCV001281307	uncertain significance	Neurofibromatosis, familial spinal	2018-01-15	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001082296	SCV001281308	uncertain significance	Neurofibromatosis, type 1	2018-01-15	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001122582	SCV001281309	uncertain significance	Neurofibromatosis-Noonan syndrome	2018-01-15	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000214790	SCV002041524	benign	not specified	2021-11-30	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.6866C>T (p.Pro2289Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251474 control chromosomes, predominantly at a frequency of 0.0052 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 25 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 phenotype (0.00021), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.6866C>T has been reported in the literature in individuals affected with various cancers (Jones_2015, Johnston_2012, Chitalia_2019), however these reports do not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1 or other cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed this variant after 2014: Four have classified this variant as likely benign/benign, and two as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000034587	SCV002063600	likely benign	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000214790	SCV002070403	likely benign	not specified	2020-08-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129366	SCV002530170	likely benign	Hereditary cancer-predisposing syndrome	2021-02-06	criteria provided, single submitter	curation
Ambry Genetics	RCV002362613	SCV002665608	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2018-10-12	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.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034587	SCV000043392	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004549402	SCV000806304	likely benign	NF1-related disorder	2020-01-31	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
GenomeConnect - Brain Gene Registry	RCV003233080	SCV003931184	not provided	Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis		no assertion provided	phenotyping only	Variant classified as Uncertain significance and reported on 02-23-2021 by Sema4. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.