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NM_058216.3(RAD51C):c.705G>T (p.Lys235Asn) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Mar 20, 2024
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:
RCV000220144.9

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:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000274447Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Mar 20, 2024) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Comprehensive Functional Characterization and Clinical Interpretation of 20 Splice-Site Variants of the RAD51C Gene.

Sanoguera-Miralles L, Valenzuela-Palomo A, Bueno-Martínez E, Llovet P, Díez-Gómez B, Caloca MJ, Pérez-Segura P, Fraile-Bethencourt E, Colmena M, Carvalho S, Allen J, Easton DF, Devilee P, Vreeswijk MPG, de la Hoya M, Velasco EA.

Cancers (Basel). 2020 Dec 15;12(12). doi:pii: E3771. 10.3390/cancers12123771.

PubMed [citation]
PMID:
33333735
PMCID:
PMC7765170

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]
PMID:
33471991
PMCID:
PMC7611105
See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000274447.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

The c.705G>T variant (also known as p.K235N), located in coding exon 4 of the RAD51C gene, results from a G to T substitution at nucleotide position 705. The amino acid change results in lysine to asparagine at codon 235, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. This variant was reported in 1/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was also reported in multiple individuals with a personal history of ovarian cancer in the French Canadian population (Alenezi WM et al. Cancers (Basel), 2022 Apr;14). RNA studies from lymphoblastoid cell lines (LCLs) from the carrier of this alteration showed absence of the entire exon 4 (Alenezi WM et al. Cancers (Basel), 2022 Apr;14). In another RNA study, this variant was associated with exon 4 skipping (Sanoguera-Miralles L et al. Cancers (Basel), 2020 Dec;12). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024