Submissions for variant NM_024675.4(PALB2):c.2128A>G (p.Thr710Ala)

gnomAD frequency: 0.00008  dbSNP: rs730881887

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160838	SCV000211512	uncertain significance	not provided	2024-10-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22941656, 25085752)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232377	SCV000290827	uncertain significance	Familial cancer of breast	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 710 of the PALB2 protein (p.Thr710Ala). This variant is present in population databases (rs730881887, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 182765). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000569204	SCV000663304	likely benign	Hereditary cancer-predisposing syndrome	2024-05-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000569204	SCV000685922	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-25	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 710 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/31398 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in 3/2559 African American women older than age 70 years with no personal history of cancer (FLOSSIES, https://whi.color.com/variant/16-23641347-T-C). Although there is a suspicion that this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance
Counsyl	RCV000232377	SCV000785518	uncertain significance	Familial cancer of breast	2017-11-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780572	SCV000917961	uncertain significance	not specified	2018-11-19	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2128A>G (p.Thr710Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 30974 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2128A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002485000	SCV002790809	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-02-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000232377	SCV004019140	likely benign	Familial cancer of breast	2023-03-30	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
PreventionGenetics, part of Exact Sciences	RCV004535048	SCV004115550	uncertain significance	PALB2-related disorder	2023-09-05	criteria provided, single submitter	clinical testing	The PALB2 c.2128A>G variant is predicted to result in the amino acid substitution p.Thr710Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.023% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-23641347-T-C). In ClinVar, this variant is interpreted as uncertain (7) and likely benign (1) (https://www.ncbi.nlm.nih.gov/clinvar/variation/182765/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000232377	SCV005053893	uncertain significance	Familial cancer of breast	2024-02-13	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000780572	SCV003839803	uncertain significance	not specified	2022-09-07	no assertion criteria provided	clinical testing	DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.2128A>G, in exon 5 that results in an amino acid change, p.Thr710Ala. This sequence change does not appear to have been previously described in individuals with PALB2-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.006% in the overall population (dbSNP rs730881887). The p.Thr710Ala change affects a highly conserved amino acid residue. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr710Ala substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Thr710Ala change remains unknown at this time.