NM_058216.3(RAD51C):c.705G>T (p.Lys235Asn) AND Fanconi anemia complementation group O

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 18, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000199916.14

Allele description [Variation Report for NM_058216.3(RAD51C):c.705G>T (p.Lys235Asn)]

NM_058216.3(RAD51C):c.705G>T (p.Lys235Asn)

Genes:

LOC129390903:MPRA-validated peak2919 silencer [Gene]
RAD51C:RAD51 paralog C [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q22

Genomic location:

Preferred name:

NM_058216.3(RAD51C):c.705G>T (p.Lys235Asn)

HGVS:

NC_000017.11:g.58703329G>T
NG_023199.1:g.15728G>T
NM_058216.3:c.705G>TMANE SELECT
NP_478123.1:p.Lys235Asn
LRG_314t1:c.705G>T
LRG_314:g.15728G>T
NC_000017.10:g.56780690G>T
NM_058216.1:c.705G>T
NM_058216.2:c.705G>T
NR_103872.2:n.580G>T

Protein change:

K235N

Links:

dbSNP: rs755849719

NCBI 1000 Genomes Browser:

rs755849719

Molecular consequence:

NM_058216.3:c.705G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_103872.2:n.580G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Fanconi anemia complementation group O
Identifiers:: MONDO: MONDO:0013248; MedGen: C3150653; Orphanet: 84; OMIM: 613390

Recent activity

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RecName: Full=Serine/threonine-protein kinase VRK2; AltName: Full=Vaccinia-relat...
RecName: Full=Serine/threonine-protein kinase VRK2; AltName: Full=Vaccinia-related kinase 2
gi|90116515|sp|Q86Y07.3|VRK2_HUMAN

Protein
kin of IRRE-like protein 2 isoform X1 [Felis catus]
kin of IRRE-like protein 2 isoform X1 [Felis catus]
gi|2131058388|ref|XP_019674254.3|

Protein
Enterobacter ludwigii strain EN-119 scaffold2, whole genome shotgun sequence
Enterobacter ludwigii strain EN-119 scaffold2, whole genome shotgun sequence
gi|748767552|ref|NZ_JTLO01000002.1| WGS:NZ_JTLO01|scaffold2

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000255192	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 18, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17576681, 9536098, 33333735, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000255192

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 18, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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

Citations

PubMed

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000255192.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 235 of the RAD51C protein (p.Lys235Asn). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. ClinVar contains an entry for this variant (Variation ID: 216807). 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 tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 33333735; Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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: Sep 29, 2024

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