chr17-58734199-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_058216.3(RAD51C):c.1108C>T(p.Arg370*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,612,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R370R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

RAD51C
NM_058216.3 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 3.04

Publications

2 publications found

Variant links:

Genes affected

RAD51C (HGNC:9820): (RAD51 paralog C) This gene is a member of the RAD51 family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51 and are known to be involved in the homologous recombination and repair of DNA. This protein can interact with other RAD51 paralogs and is reported to be important for Holliday junction resolution. Mutations in this gene are associated with Fanconi anemia-like syndrome. This gene is one of four localized to a region of chromosome 17q23 where amplification occurs frequently in breast tumors. Overexpression of the four genes during amplification has been observed and suggests a possible role in tumor progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

RAD51C Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 3
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
Fanconi anemia complementation group O
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RAD51C links:

LOC105371843 (HGNC:):

LOC105371843 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0203 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD51C	NM_058216.3 link	c.1108C>T	p.Arg370*	stop_gained	Exon 9 of 9	ENST00000337432.9	NP_478123.1	O43502-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD51C	ENST00000337432.9 link	c.1108C>T	p.Arg370*	stop_gained	Exon 9 of 9	1	NM_058216.3	ENSP00000336701.4		O43502-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

248636

AF XY:

0.00000745

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000582

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460370

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.0000449

AC:

AN:

44592

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26026

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000233

AC:

AN:

86000

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111182

Other (OTH)

AF:

0.00

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jun 18, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation as the last 7 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 12966089, 14704354, 37298034, 34570441, 32809180, 35171259) -

Oct 22, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The RAD51C c.1108C>T (p.Arg370*) variant is predicted to cause a premature stop codon in the last exon. This is not expected to result in nonsense-mediated decay, although it is predicted to truncate the protein by 7 amino acids. The potential impact of this alteration on protein function is unclear. This variant has been reported in the published literature in individuals with breast or pancreatic cancer (PMIDs: 35171259 (2022), 34570441 (2021), 32809180 (2020)). The frequency of this variant in the general population, 0.000014 (4/280040 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Jul 19, 2021

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant changes 1 nucleotide in exon 9 of the RAD51C gene, creating a premature translation stop signal in the last coding exon. While this mutant transcript is predicted to escape nonsense-mediated decay, it is expected to delete 7 amino acids from the C-terminus of the RAD51C protein. While to our knowledge, functional studies have not been reported for this variant, cells with a variant protein missing the 11 amino acids from the C-terminus have been reported to have reduced mitomycin C resistance (PMID: 12966089). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/280040 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. -

Jan 02, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R370* variant (also known as c.1108C>T) located in coding exon 9 of the RAD51C gene, results from a C to T substitution at nucleotide position 1108. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration was detected in a cohort of 116 patients from Chinese familial breast cancer families (Dong L et al. Cancer Biol Med, 2021 Sep;19:850-70). This alteration occurs at the 3' terminus of the RAD51C gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last seven amino acids of the protein. The exact functional effect of this alteration is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Breast-ovarian cancer, familial, susceptibility to, 3

Uncertain:2

Dec 27, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 07, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

May 23, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RAD51C c.1108C>T (p.Arg370X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, and no downtream pathogenic variants have been reported. The variant allele was found at a frequency of 1.2e-05 in 248636 control chromosomes. c.1108C>T has been reported in the literature in individuals affected with Breast Cancer, Pancreatic ductal adenocarcinoma and Acute pancreatitis, without strong evidence for causality (Bagherzadeh_2020, Dong_2022, Yin_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32809180, 34570441, 35171259). ClinVar contains an entry for this variant (Variation ID: 187300). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Fanconi anemia complementation group O

Uncertain:1

Nov 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg370*) in the RAD51C gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 7 amino acid(s) of the RAD51C protein. This variant is present in population databases (rs756744016, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 32809180, 34570441). ClinVar contains an entry for this variant (Variation ID: 187300). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.81

PhyloP100

3.0

Vest4

0.71

ClinPred

1.0

GERP RS

4.4

Mutation Taster

=63/137

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over