Submissions for variant NM_024675.4(PALB2):c.2120del (p.Pro707fs)

dbSNP: rs587780210

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254677	SCV000149988	pathogenic	not provided	2023-05-11	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Nguyen-Dumont et al., 2015; Maxwell et al., 2016; Susswein et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 25575445, 26681312, 27153395, 31447099, 29922827)
Ambry Genetics	RCV000116079	SCV000278671	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-21	criteria provided, single submitter	clinical testing	The c.2120delC pathogenic mutation, located in coding exon 5 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 2120, causing a translational frameshift with a predicted alternate stop codon (p.P707Lfs*2). This alteration was reported in a woman diagnosed with breast cancer at age 62 from a cohort of 1250 families enrolled in the Breast Cancer Family Registry (Nguyen-Dumont T et al. Breast Cancer Res.Treat. 2015 Jan;149(2):547-54). This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet Med. 2016 8;18(8):823-32.). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Counsyl	RCV000409069	SCV000489423	pathogenic	Familial cancer of breast	2016-10-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409069	SCV000550717	pathogenic	Familial cancer of breast	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro707Leufs*2) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is present in population databases (rs587780210, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer and thyroid cancer and breast cancer (PMID: 25575445, 26681312). ClinVar contains an entry for this variant (Variation ID: 128128). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000254677	SCV000601750	pathogenic	not provided	2017-05-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116079	SCV000685920	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 5 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer, and in an individual affected with breast cancer and thyroid cancer (PMID: 25575445, 26681312; Color internal data). This variant has been identified in 2/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258078	SCV001434917	pathogenic	Pancreatic cancer, susceptibility to, 3; Breast cancer, susceptibility to	2018-10-14	criteria provided, single submitter	clinical testing	The c.2120delC (p.Pro707Leufs*2) variant in the PALB2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in two patients affected with breast cancer (PMID 25575445, 26681312) and is extremely rare in general population databases. Therefore, this c.2120delC (p,Pro707Leus*2) variant in the PALB2 gene is classified as pathogenic.
Myriad Genetics, Inc.	RCV000409069	SCV004019696	pathogenic	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV000409069	SCV004202619	pathogenic	Familial cancer of breast	2024-01-08	criteria provided, single submitter	clinical testing