NM_058216.3(RAD51C):c.644A>G (p.Asp215Gly) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 3, 2023
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:: RCV002365893.3

Allele description [Variation Report for NM_058216.3(RAD51C):c.644A>G (p.Asp215Gly)]

NM_058216.3(RAD51C):c.644A>G (p.Asp215Gly)

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.644A>G (p.Asp215Gly)

HGVS:

NC_000017.11:g.58703268A>G
NG_023199.1:g.15667A>G
NM_058216.3:c.644A>GMANE SELECT
NP_478123.1:p.Asp215Gly
LRG_314t1:c.644A>G
LRG_314:g.15667A>G
NC_000017.10:g.56780629A>G
NM_058216.1:c.644A>G
NM_058216.2:c.644A>G
NR_103872.2:n.519A>G

Protein change:

D215G

Links:

dbSNP: rs1483938000

NCBI 1000 Genomes Browser:

rs1483938000

Molecular consequence:

NM_058216.3:c.644A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_103872.2:n.519A>G - 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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Nucleotide RefSeq for Assembly (Select 7046201) (13)
Nucleotide
PREDICTED: Chlorocebus sabaeus interferon regulatory factor 9 (IRF9), transcript...
PREDICTED: Chlorocebus sabaeus interferon regulatory factor 9 (IRF9), transcript variant X1, mRNA
gi|1938814097|ref|XM_007986291.2|

Nucleotide
Profile neighbors for GEO Profiles (Select 1007489) (41)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002659629	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Sep 16, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21597919, 31742824 Citation Link,
SCV004357117	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 3, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 2159791, 31742824, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002659629

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Sep 16, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV004357117

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 3, 2023)

germline

clinical testing

PubMed (3)
[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

Hairpin structures in DNA containing arabinofuranosylcytosine. A combination of nuclear magnetic resonance and molecular dynamics.

Pieters JM, de Vroom E, van der Marel GA, van Boom JH, Koning TM, Kaptein R, Altona C.

Biochemistry. 1990 Jan 23;29(3):788-99.

PubMed [citation]

PMID:: 2159791

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV002659629.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.D215G variant (also known as c.644A>G), located in coding exon 4 of the RAD51C gene, results from an A to G substitution at nucleotide position 644. The aspartic acid at codon 215 is replaced by glycine, an amino acid with similar properties. This alteration was identified in 1/273 familial breast cancer cases and 0/475 controls (Pang Z et al. Breast Cancer Res Treat, 2011 Oct;129:1019-20). This variant was also identified in a cohort of 882 Chinese individuals with a personal and/or family history of breast or ovarian cancers who underwent multi-gene panel testing for HBOC risk assessment (Shao D et al. Cancer Sci, 2020 Feb;111:647-657). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration 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, SCV004357117.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces aspartic acid with glycine at codon 215 of the RAD51C protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 2159791) and in an individual affected with hereditary breast and ovarian cancer (PMID: 31742824). This variant has been identified in 1/251266 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of 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: May 1, 2024

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