NM_058216.3(RAD51C):c.571+5G>A AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Nov 26, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000561973.14

Allele description [Variation Report for NM_058216.3(RAD51C):c.571+5G>A]

NM_058216.3(RAD51C):c.571+5G>A

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.571+5G>A

HGVS:

NC_000017.11:g.58696864G>A
NG_023199.1:g.9263G>A
NG_047169.1:g.216C>T
NM_058216.3:c.571+5G>AMANE SELECT
LRG_314t1:c.571+5G>A
LRG_314:g.9263G>A
NC_000017.10:g.56774225G>A
NM_058216.1:c.571+5G>A
NM_058216.2:c.571+5G>A

Links:

dbSNP: rs145779113

NCBI 1000 Genomes Browser:

rs145779113

Molecular consequence:

NM_058216.3:c.571+5G>A - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000663769	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Nov 26, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21597919, 29278735, 30093976, 33333735 Citation Link,
SCV000691251	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 20, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21597919, 29278735, 30093976, 33333735, 36909564, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000663769

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Nov 26, 2024)

germline

clinical testing

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

Citation Link,

SCV000691251

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 20, 2024)

germline

clinical testing

PubMed (6)
[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

RAD51C germline mutations in Chinese women with familial breast cancer.

Pang Z, Yao L, Zhang J, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, Xie Y.

Breast Cancer Res Treat. 2011 Oct;129(3):1019-20. doi: 10.1007/s10549-011-1574-3. Epub 2011 May 20. No abstract available.

PubMed [citation]

PMID:: 21597919

Expanding the FANCO/RAD51C associated phenotype: Cleft lip and palate and lobar holoprosencephaly, two rare findings in Fanconi anemia.

Jacquinet A, Brown L, Sawkins J, Liu P, Pugash D, Van Allen MI, Patel MS.

Eur J Med Genet. 2018 May;61(5):257-261. doi: 10.1016/j.ejmg.2017.12.011. Epub 2017 Dec 24.

PubMed [citation]

PMID:: 29278735

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000663769.7

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

Description

The c.571+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 3 in the RAD51C gene. This alteration was reported in 1/273 Chinese women with familial breast cancer who previously tested BRCA1/2 negative and also reported in an individual affected with ovarian cancer (Pang Z et al. Breast Cancer Res. Treat., 2011 Oct;129:1019-20; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660). Additionally, this variant has been reported in conjunction with another variant in RAD51C in an individual diagnosed with clinical features of Fanconi anemia (Jacquinet A et al. Eur J Med Genet, 2018 May;61:257-261). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies in the literature have demonstrated that this alteration results in impaired splicing (Sanoguera-Miralles L et al. Cancers (Basel), 2020 Dec;12:). Internal RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). Based on the available evidence, the clinical significance of this variant remains unclear.

#	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

From Color Diagnostics, LLC DBA Color Health, SCV000691251.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This variant causes a G>A nucleotide substitution at the +5 position of intron 3 of the RAD51C gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A mini-gene splice assay has shown that this variant results in out-of-frame skipping of exon 3 in over 90% of the transcripts (PMID: 33333735). This variant is expected to result in an absent or non-functional protein product. This variant has been observed in an individual affected with ovarian cancer (PMID: 30093976), in two individuals affected with breast cancer (PMID: 21597919; Lertwilaiwittaya et al., 2020, DOI: https://doi.org/10.21203/rs.3.rs-122156/v1), and in an individual having clinical features of Fanconi anemia (PMID: 29278735, 36909564). All of these affected individuals were of East Asian ethnicity. This variant has been identified in 7/282860 chromosomes (7/19250 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51C function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is 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: May 16, 2025

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