rs515726123

Variant names:

• chr16-23636035-ATC-A
• rs515726123
• NM_024675.4:c.509_510delGA

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 18 classification points (ACMG Germline Pathogenicity v2019). PVS1PS3PM2PP5_Strong

The NM_024675.4(PALB2):c.509_510delGA (p.Arg170IlefsTer14) variant causes a frameshift change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.0000186 (AC=30) in the gnomAD database across 1,614,006 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000166. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001366810: PS3, PS4_STR *Note: Since the input directly mentions PS3, it is treated as providing evidence for PS3 without needing to extract a specific snippet.* However, based on the instructions and examples provided, the correct response should be: **Output**: `no`" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: PALB2 NM_024675.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:54 O:1
• Conservation: PhyloP100: -0.0180
• Publications: 10 publications found

Genes affected

PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]

PALB2 Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• PALB2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Fanconi anemia complementation group N

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Specifications for PALB2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 18 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Frameshift (exon 4 of 13) at amino acid 170 of 1186, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene. A new stop codon is introduced in the shifted frame, truncating the protein to ~182 amino acids (1004 amino acids lost).
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV001366810: PS3, PS4_STR *Note: Since the input directly mentions PS3, it is treated as providing evidence for PS3 without needing to extract a specific snippet.* However, based on the instructions and examples provided, the correct response should be: **Output**: `no`; SCV000185544: Further, a functional characterization of this alteration showed that the truncated protein results in weakly bound DNA substrates, suggesting that the loss of the second DNA binding domain affects the affinity for DNA, resulting in significantly impaired DNA binding (Pauty J et al. Nucleic Acids Res. 2017 Mar;45:2644-2657).; SCV000686065: A functional study reported that this variant impacts PALB2 binding to DNA (PMID: 28158555).; SCV000601792: Functional studies in the published literature report this variant reduced DNA binding and failed to stimulate RAD51-mediated strand invasion (PMID: 28158555 (2017)).; SCV001623425: Experimental evidence evaluating an impact on protein function demonstrated the variant impairs DNA binding ability, fails to stimulate RAD51 and fails to localize to DNA damage sites (Pauty_2017).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000166 — very rare for AD+AR gene (base 0.0001, raised to 0.000208 by highest known P/LP ClinVar AF 0.000208) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (54/54 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_024675.4. 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
	PALB2 NM_024675.4	MANE Select	c.509_510delGA p.Arg170IlefsTer14	frameshift	Exon 4 of 13	Prot: NP_078951.2
	PALB2 NM_001407296.1		c.449_450delGA p.Arg150IlefsTer14	frameshift	Exon 3 of 12	Prot: NP_001394225.1
	PALB2 NM_001407297.1		c.509_510delGA p.Arg170IlefsTer14	frameshift	Exon 4 of 12	Prot: NP_001394226.1

PALB2 NM_024675.4

MANE Select

HGVSc / HGVSpc.509_510delGAp.Arg170IlefsTer14

Exon rankExon 4 of 13

frameshift

Prot: NP_078951.2

PALB2 NM_001407296.1

HGVSc / HGVSpc.449_450delGAp.Arg150IlefsTer14

Exon rankExon 3 of 12

frameshift

Prot: NP_001394225.1

PALB2 NM_001407297.1

HGVSc / HGVSpc.509_510delGAp.Arg170IlefsTer14

Exon rankExon 4 of 12

frameshift

Prot: NP_001394226.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PALB2 ENST00000261584.9	TSL:1MANE Select	c.509_510delGA p.Arg170IlefsTer14	frameshift	Exon 4 of 13	Prot: ENSP00000261584.4 UniProt:
	PALB2 ENST00000568219.5	TSL:1	c.-377_-376delGA	5_prime_UTR	Exon 4 of 13	Prot: ENSP00000454703.2 UniProt:
	PALB2 ENST00000561514.3	TSL:5	c.515_516delGA p.Arg172IlefsTer14	frameshift	Exon 4 of 13	Prot: ENSP00000460666.3 UniProt:

PALB2 ENST00000261584.9

TSL:1MANE Select

HGVSc / HGVSpc.509_510delGAp.Arg170IlefsTer14

Exon rankExon 4 of 13

frameshift

Prot: ENSP00000261584.4UniProt: Q86YC2

PALB2 ENST00000568219.5

TSL:1

HGVSc / HGVSpc.-377_-376delGA

Exon rankExon 4 of 13

5_prime_UTR

Prot: ENSP00000454703.2UniProt: H3BN63

PALB2 ENST00000561514.3

TSL:5

HGVSc / HGVSpc.515_516delGAp.Arg172IlefsTer14

Exon rankExon 4 of 13

frameshift

Prot: ENSP00000460666.3UniProt: A0AA52I2C1

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000131	AC:2	Hom:0	AN:152126	Cov:32
GnomAD2 exomes	AF: 0.0000358	AC:9	Hom:	AN:251446	Cov:
GnomAD4 exome	AF: 0.0000192	AC:28	Hom:0	AN:1461880	Cov:
GnomAD4 genome	AF: 0.0000131	AC:2	Hom:0	AN:152126	Cov:32
TOPMed (Bravo)	AF: 0.0000113	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:17394	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000477	2	41958	0.0000299	2	66888
SCHEMA(Schizophrenia)	0.00	0	113100	0.0000263	5	190460

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
17	-	-	not provided (17)
11	-	-	Familial cancer of breast (11)
8	-	-	Hereditary cancer-predisposing syndrome (8)
3	-	-	Breast-ovarian cancer, familial, susceptibility to, 5 (3)
2	-	-	Breast and/or ovarian cancer (2)
2	-	-	Malignant tumor of breast (2)
2	-	-	PALB2-related disorder (2)
1	-	-	autosomal dominant PALB2-related cancer predisposition (1)
1	-	-	Breast carcinoma (1)
1	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (1)
1	-	-	Carcinoma of pancreas (1)
1	-	-	Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 (1)
1	-	-	Hereditary breast ovarian cancer syndrome (1)
1	-	-	Inherited breast cancer and ovarian cancer (1)
1	-	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Benign	-0.018

Showing 2 of 2 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 1 of 1 scores

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.

Other links and lift over

dbSNP: rs515726123;

hg19: chr16-23647356;

COSMIC: COSV108015612;

COSMIC: COSV108015612;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar