rs12946397

Variant names:

• chr17-58692618-C-T
• rs12946397
• NM_058216.3:c.-26C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-58692618-C-T
• chr17-58692618-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_058216.3(RAD51C):​c.-26C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,612,988 control chromosomes in the GnomAD database, including 34,610 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2768 hom., cov: 32)
  • Exomes 𝑓: 0.20 (31842 hom.)
• Consequence: RAD51C NM_058216.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.24
• Publications: 28 publications found

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, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Fanconi anemia complementation group O

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 17-58692618-C-T is Benign according to our data. Variant chr17-58692618-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 324173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	NM_058216.3	MANE Select	c.-26C>T		5_prime_UTR	Exon 1 of 9	NP_478123.1	O43502-1
	RAD51C	NM_002876.4		c.-26C>T		5_prime_UTR	Exon 1 of 2	NP_002867.1	O43502-2
	RAD51C	NR_103872.2		n.17C>T		non_coding_transcript_exon	Exon 1 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD51C	ENST00000337432.9	TSL:1 MANE Select	c.-26C>T		5_prime_UTR	Exon 1 of 9	ENSP00000336701.4	O43502-1
	RAD51C	ENST00000482007.5	TSL:1	n.-26C>T		non_coding_transcript_exon	Exon 1 of 8	ENSP00000433332.1	Q7KZJ0
	RAD51C	ENST00000482007.5	TSL:1	n.-26C>T		5_prime_UTR	Exon 1 of 8	ENSP00000433332.1	Q7KZJ0

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28080 AN: 152098 Hom.: 2765 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.0824

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.212

Gnomad OTH AF: 0.169

GnomAD2 exomes AF: 0.180 AC: 44995 AN: 250272 AF XY: 0.179

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.133

Gnomad ASJ exome AF: 0.0905

Gnomad EAS exome AF: 0.170

Gnomad FIN exome AF: 0.263

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.204 AC: 298243 AN: 1460772 Hom.: 31842 Cov.: 33 AF XY: 0.202 AC XY: 146701 AN XY: 726612

African (AFR) AF: 0.132 AC: 4406 AN: 33458

American (AMR) AF: 0.138 AC: 6155 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0890 AC: 2325 AN: 26132

East Asian (EAS) AF: 0.208 AC: 8254 AN: 39696

South Asian (SAS) AF: 0.139 AC: 11971 AN: 86154

European-Finnish (FIN) AF: 0.261 AC: 13871 AN: 53140

Middle Eastern (MID) AF: 0.113 AC: 599 AN: 5312

European-Non Finnish (NFE) AF: 0.216 AC: 239838 AN: 1111838

Other (OTH) AF: 0.179 AC: 10824 AN: 60328

GnomAD4 genome AF: 0.185 AC: 28097 AN: 152216 Hom.: 2768 Cov.: 32 AF XY: 0.187 AC XY: 13935 AN XY: 74418

African (AFR) AF: 0.137 AC: 5679 AN: 41564

American (AMR) AF: 0.176 AC: 2699 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0824 AC: 286 AN: 3472

East Asian (EAS) AF: 0.177 AC: 915 AN: 5168

South Asian (SAS) AF: 0.139 AC: 671 AN: 4828

European-Finnish (FIN) AF: 0.264 AC: 2791 AN: 10572

Middle Eastern (MID) AF: 0.0856 AC: 25 AN: 292

European-Non Finnish (NFE) AF: 0.212 AC: 14386 AN: 67994

Other (OTH) AF: 0.167 AC: 352 AN: 2114

Alfa AF: 0.187 Hom.: 754

Bravo AF: 0.170

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Breast and Ovarian Cancer Susceptibility (1)
-	-	1	Fanconi anemia (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	RAD51C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.74
DANN	Benign	0.88
PhyloP100		-3.2
PromoterAI		0.33	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12946397; hg19: chr17-56769979; COSMIC: COSV53625930; COSMIC: COSV53625930;