NM_002880.4(RAF1):c.1927C>T (p.Pro643Ser) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 16, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000220865.5

Allele description [Variation Report for NM_002880.4(RAF1):c.1927C>T (p.Pro643Ser)]

NM_002880.4(RAF1):c.1927C>T (p.Pro643Ser)

Gene:

RAF1:Raf-1 proto-oncogene, serine/threonine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p25.2

Genomic location:

Preferred name:

NM_002880.4(RAF1):c.1927C>T (p.Pro643Ser)

HGVS:

NC_000003.12:g.12584534G>A
NG_007467.1:g.84646C>T
NM_001354689.3:c.1987C>T
NM_001354690.3:c.1927C>T
NM_001354691.3:c.1684C>T
NM_001354692.3:c.1684C>T
NM_001354693.3:c.1828C>T
NM_001354694.3:c.1744C>T
NM_001354695.3:c.1585C>T
NM_002880.4:c.1927C>TMANE SELECT
NP_001341618.1:p.Pro663Ser
NP_001341619.1:p.Pro643Ser
NP_001341620.1:p.Pro562Ser
NP_001341621.1:p.Pro562Ser
NP_001341622.1:p.Pro610Ser
NP_001341623.1:p.Pro582Ser
NP_001341624.1:p.Pro529Ser
NP_002871.1:p.Pro643Ser
NP_002871.1:p.Pro643Ser
LRG_413t1:c.1927C>T
LRG_413t2:c.1987C>T
LRG_413:g.84646C>T
LRG_413p1:p.Pro643Ser
LRG_413p2:p.Pro663Ser
NC_000003.11:g.12626033G>A
NM_002880.3:c.1927C>T
NR_148940.3:n.2371C>T
NR_148941.3:n.2317C>T
NR_148942.3:n.2256C>T

Protein change:

P529S

Links:

dbSNP: rs876657967

NCBI 1000 Genomes Browser:

rs876657967

Molecular consequence:

NM_001354689.3:c.1987C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354690.3:c.1927C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354691.3:c.1684C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354692.3:c.1684C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354693.3:c.1828C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354694.3:c.1744C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354695.3:c.1585C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002880.4:c.1927C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_148940.3:n.2371C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148941.3:n.2317C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148942.3:n.2256C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000272344	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Dec 22, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002555923	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jun 16, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000272344

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Dec 22, 2015)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002555923

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jun 16, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000272344.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

The p.Pro643Ser variant in RAF1 has not been previously reported in individuals with a RASopathy disorder and was absent from large population studies. Proline (Pro) at position 643 is not conserved in mammals or evolutionarily distant spec ies and 2 species (bactrian camel, ground finch) carry a serine (Ser) at this po sition, raising the possibility that this change may be tolerated. In summary, t he clinical significance of the p.Pro643Ser variant is uncertain.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002555923.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Variant summary: RAF1 c.1927C>T (p.Pro643Ser) results in a non-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 was absent in 251246 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1927C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 24, 2022

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