Genetic Variant RAD51C:p.Gly149Ala (chr17-58696734-GA-CG) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is The variant received 3 classification points (ACMG Germline Pathogenicity v2019). PM1_SupportingPM2

The NM_058216.3(RAD51C):c.446_447delGAinsCG (p.Gly149Ala) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.84). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.G149E: Uncertain_significance (ClinVar VariationId 538761, 2 stars); p.G149= (synonymous): Benign (ClinVar VariationId 3903704, 1 star); p.G149= (synonymous): Likely_benign (ClinVar VariationId 1740875, 2 stars)

Frequency

Genomes: not found (cov: 32)

Consequence

RAD51C
NM_058216.3 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.84

Publications

0 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):

RAD51C-related cancer predisposition
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RAD51C links:

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new If you want to explore the variant's impact on the transcript NM_058216.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 3 points.

Show applied only (2)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood moderate hotspot (≥2 P/LP within ±8 AA, OR ≥ 2 vs. background) — PM1 supporting; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 5 pathogenic, 9 benign (OR vs. background: 2.9).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_058216.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RAD51C NM_058216.3	MANE Select	c.446_447delGAinsCG p.Gly149Ala	missense	N/A	Prot: NP_478123.1 UniProt: O43502-1
	RAD51C NR_103872.2		n.446+1545_446+1546delGAinsCG	intron	Intron 2 of 7	Prot:

RAD51C NM_058216.3

MANE Select

HGVSc / HGVSpc.446_447delGAinsCGp.Gly149Ala

Exon rankN/A

missense

Prot: NP_478123.1UniProt: O43502-1

RAD51C NR_103872.2

HGVSc / HGVSpn.446+1545_446+1546delGAinsCG

Exon rankIntron 2 of 7

intron

Prot:

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
RAD51C ENST00000337432.9	TSL:1MANE Select	c.446_447delGAinsCG p.Gly149Ala	missense	N/A	Prot: ENSP00000336701.4 UniProt: O43502-1
RAD51C ENST00000482007.5	TSL:1	n.404+1545_404+1546delGAinsCG	intron	Intron 2 of 7	Prot: ENSP00000433332.1 UniProt: F6SK77
RAD51C ENST00000930423.1		c.446_447delGAinsCG p.Gly149Ala	missense	N/A	Prot: ENSP00000600482.1 UniProt: A0ACI8TKF8

RAD51C ENST00000337432.9

TSL:1MANE Select

HGVSc / HGVSpc.446_447delGAinsCGp.Gly149Ala

Exon rankN/A

missense

Prot: ENSP00000336701.4UniProt: O43502-1

RAD51C ENST00000482007.5

TSL:1

HGVSc / HGVSpn.404+1545_404+1546delGAinsCG

Exon rankIntron 2 of 7

intron

Prot: ENSP00000433332.1UniProt: F6SK77

RAD51C ENST00000930423.1

HGVSc / HGVSpc.446_447delGAinsCGp.Gly149Ala

Exon rankN/A

missense

Prot: ENSP00000600482.1UniProt: A0ACI8TKF8

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	8.8

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence