chr17-35100447-AGCTTATTTCCACCCAGTAACTCAGAGACAGAGCTAAGGAAGAGTGGGCCCCCATCTAACAAATGGAAAGGCAGAGACAAAAGAAAAAAAAGGCAGCAGCAGCAAAGGCAAGTTAGAGGCTTTCCCGGCTTGGCCACTGCGCTAGGAGGGAGCACAGGACACAATGGTGATGCACAGGATTATCCATCCAGTCGCCAGCATGCCTCATCAGAGATGCTCCCAGCCAGGGTGAACTTGGTTTCCACCAGAAACATACACGTTAGAAATAAGGGAAGGAAACGTGGCACCAGTATGAATTTCTGGGTCCTCGCAATGCAGCATCCTCTTTCGCCTGTGGTTTATATGCTTACAGAGAGTGAGGCCAAGGAACCCAAGATGTCTCTTCTGGCCAGCCTGAGAACGTCTGTAGTCACCAGTGCCAGGTGGCAGTAAACAGCAGGCGTTACTGGGAAGAAAAGTTGGGAGGGGTCCCCAATGCTTCCCTGTTTCCCAAACAACAGCACAGGTCATGTCTGATCACCCTGTAATGTGGCACTCTGCTCTGAGGTCCCCCAGGTCCCAATGTCTACCATCTCCTGGAAACCTGTTGGCTGGAAGAAGAAGTAAGGAGTCAGTGGAGTTAAGCAACCCAAGTGGGTAGCTTCTTTAGTTGCAAGGTTTCAGCCTCTAAAGAGTTCTTCTCGAAGACATCTGTGGGTATGGAAACCACCCTCCAGGGCCCAAGATTACTGGCATCTTCCTGGGGCTGGCTCACCTGTCGGG-A

Position:

• chr17-35100447-AGCTTATTTCCACCCAGTAACTCAGAGACAGAGCTAAGGAAGAGTGGGCCCCCATCTAACAAATGGAAAGGCAGAGACAAAAGAAAAAAAAGGCAGCAGCAGCAAAGGCAAGTTAGAGGCTTTCCCGGCTTGGCCACTGCGCTAGGAGGGAGCACAGGACACAATGGTGATGCACAGGATTATCCATCCAGTCGCCAGCATGCCTCATCAGAGATGCTCCCAGCCAGGGTGAACTTGGTTTCCACCAGAAACATACACGTTAGAAATAAGGGAAGGAAACGTGGCACCAGTATGAATTTCTGGGTCCTCGCAATGCAGCATCCTCTTTCGCCTGTGGTTTATATGCTTACAGAGAGTGAGGCCAAGGAACCCAAGATGTCTCTTCTGGCCAGCCTGAGAACGTCTGTAGTCACCAGTGCCAGGTGGCAGTAAACAGCAGGCGTTACTGGGAAGAAAAGTTGGGAGGGGTCCCCAATGCTTCCCTGTTTCCCAAACAACAGCACAGGTCATGTCTGATCACCCTGTAATGTGGCACTCTGCTCTGAGGTCCCCCAGGTCCCAATGTCTACCATCTCCTGGAAACCTGTTGGCTGGAAGAAGAAGTAAGGAGTCAGTGGAGTTAAGCAACCCAAGTGGGTAGCTTCTTTAGTTGCAAGGTTTCAGCCTCTAAAGAGTTCTTCTCGAAGACATCTGTGGGTATGGAAACCACCCTCCAGGGCCCAAGATTACTGGCATCTTCCTGGGGCTGGCTCACCTGTCGGG-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_002878.4(RAD51D):​c.896_*505del variant causes a splice acceptor, splice donor, stop lost, splice donor 5th base, 3 prime UTR, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. SRQPTGFQEMVDIGTWGTSEQSATLQGDQT*299?) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD51D NM_002878.4 splice_acceptor, splice_donor, stop_lost, splice_donor_5th_base, 3_prime_UTR, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.79

Genes affected

RAD51D (HGNC:9823): (RAD51 paralog D) The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51, which are known to be involved in the homologous recombination and repair of DNA. This protein forms a complex with several other members of the RAD51 family, including RAD51L1, RAD51L2, and XRCC2. The protein complex formed with this protein has been shown to catalyze homologous pairing between single- and double-stranded DNA, and is thought to play a role in the early stage of recombinational repair of DNA. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream ring finger and FYVE-like domain containing 1 (RFFL) gene. [provided by RefSeq, Jan 2011]

RAD51L3-RFFL (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates 0.09219858156028371 fraction of the gene
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-35100447-AGCTTATTTCCACCCAGTAACTCAGAGACAGAGCTAAGGAAGAGTGGGCCCCCATCTAACAAATGGAAAGGCAGAGACAAAAGAAAAAAAAGGCAGCAGCAGCAAAGGCAAGTTAGAGGCTTTCCCGGCTTGGCCACTGCGCTAGGAGGGAGCACAGGACACAATGGTGATGCACAGGATTATCCATCCAGTCGCCAGCATGCCTCATCAGAGATGCTCCCAGCCAGGGTGAACTTGGTTTCCACCAGAAACATACACGTTAGAAATAAGGGAAGGAAACGTGGCACCAGTATGAATTTCTGGGTCCTCGCAATGCAGCATCCTCTTTCGCCTGTGGTTTATATGCTTACAGAGAGTGAGGCCAAGGAACCCAAGATGTCTCTTCTGGCCAGCCTGAGAACGTCTGTAGTCACCAGTGCCAGGTGGCAGTAAACAGCAGGCGTTACTGGGAAGAAAAGTTGGGAGGGGTCCCCAATGCTTCCCTGTTTCCCAAACAACAGCACAGGTCATGTCTGATCACCCTGTAATGTGGCACTCTGCTCTGAGGTCCCCCAGGTCCCAATGTCTACCATCTCCTGGAAACCTGTTGGCTGGAAGAAGAAGTAAGGAGTCAGTGGAGTTAAGCAACCCAAGTGGGTAGCTTCTTTAGTTGCAAGGTTTCAGCCTCTAAAGAGTTCTTCTCGAAGACATCTGTGGGTATGGAAACCACCCTCCAGGGCCCAAGATTACTGGCATCTTCCTGGGGCTGGCTCACCTGTCGGG-A is Pathogenic according to our data. Variant chr17-35100447-AGCTTATTTCCACCCAGTAACTCAGAGACAGAGCTAAGGAAGAGTGGGCCCCCATCTAACAAATGGAAAGGCAGAGACAAAAGAAAAAAAAGGCAGCAGCAGCAAAGGCAAGTTAGAGGCTTTCCCGGCTTGGCCACTGCGCTAGGAGGGAGCACAGGACACAATGGTGATGCACAGGATTATCCATCCAGTCGCCAGCATGCCTCATCAGAGATGCTCCCAGCCAGGGTGAACTTGGTTTCCACCAGAAACATACACGTTAGAAATAAGGGAAGGAAACGTGGCACCAGTATGAATTTCTGGGTCCTCGCAATGCAGCATCCTCTTTCGCCTGTGGTTTATATGCTTACAGAGAGTGAGGCCAAGGAACCCAAGATGTCTCTTCTGGCCAGCCTGAGAACGTCTGTAGTCACCAGTGCCAGGTGGCAGTAAACAGCAGGCGTTACTGGGAAGAAAAGTTGGGAGGGGTCCCCAATGCTTCCCTGTTTCCCAAACAACAGCACAGGTCATGTCTGATCACCCTGTAATGTGGCACTCTGCTCTGAGGTCCCCCAGGTCCCAATGTCTACCATCTCCTGGAAACCTGTTGGCTGGAAGAAGAAGTAAGGAGTCAGTGGAGTTAAGCAACCCAAGTGGGTAGCTTCTTTAGTTGCAAGGTTTCAGCCTCTAAAGAGTTCTTCTCGAAGACATCTGTGGGTATGGAAACCACCCTCCAGGGCCCAAGATTACTGGCATCTTCCTGGGGCTGGCTCACCTGTCGGG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1516502.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD51D	NM_002878.4	c.896_*505del		splice_acceptor_variant, splice_donor_variant, stop_lost, splice_donor_5th_base_variant, 3_prime_UTR_variant, intron_variant	9/10	ENST00000345365.11
RAD51L3-RFFL	NR_037714.1	n.648_655+753del		splice_donor_variant, splice_donor_5th_base_variant, non_coding_transcript_exon_variant, intron_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD51D	ENST00000345365.11	c.896_*505del		splice_acceptor_variant, splice_donor_variant, stop_lost, splice_donor_5th_base_variant, 3_prime_UTR_variant, intron_variant	9/10	1	NM_002878.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 14, 2021

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This partial deletion is expected to delete amino acid residues Ser299-Thr328 of the RAD51D protein, thereby removing the C-terminus of the ATPase domain (PMID: 14704354, 19327148, 21111057). Although functional studies have not been done for this particular deletion, experimental studies using yeast two-hybrid analysis have shown that the region of the RAD51D protein necessary for RAD51C complexing localizes to the last ~100 amino acids (PMID: 10749867, 14704354, 19327148). The data indicates that this deletion likely disrupts this important RAD51D-RAD51C interaction. While this particular deletion has not been reported in the literature, a gross deletion of exon 10 has been observed in an individual affected with breast cancer (PMID: 26681312). This variant is a gross deletion of the genomic region encompassing the last 8 nucleotides of exon 9 and exon 10 of the RAD51D gene (c.896_*505del). While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein product or disrupt mRNA translation. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-33427466;