Submissions for variant NM_024675.4(PALB2):c.2641G>A (p.Gly881Ser)

gnomAD frequency: 0.00003  dbSNP: rs766315705

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549911	SCV000633363	uncertain significance	Familial cancer of breast	2022-09-14	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 881 of the PALB2 protein (p.Gly881Ser). This variant is present in population databases (rs766315705, gnomAD 0.005%). This missense change has been observed in individual(s) with pancreatic and breast cancer (PMID: 25356972, 30287823). ClinVar contains an entry for this variant (Variation ID: 460951). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PALB2 protein function. 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	RCV000572967	SCV000663379	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-27	criteria provided, single submitter	clinical testing	The p.G881S variant (also known as c.2641G>A), located in coding exon 7 of the PALB2 gene, results from a G to A substitution at nucleotide position 2641. The glycine at codon 881 is replaced by serine, an amino acid with similar properties. This variant was identified in 1/727 pancreatic cancer probands with positive family history and classified as a variant of uncertain significance by the study authors (Zhen DB et al. Genet. Med., 2015 Jul;17:569-77). This alteration has also been reported in at least one breast cancer patient in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000572967	SCV000685966	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-07	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 881 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 now shown significant association with breast cancer in case-control studies: In one study, this variant was observed in 1/7051 female cases and 2/11241 female controls, as well as in 0/53 male cases and 3/12490 male controls (PMID: 30287823). In a meta-analysis of breast cancer case-control studies, this variant was reported in 4/60462 cases and 3/53458 controls (PMID: 33471991). This variant has been reported in an individual with pancreatic cancer (PMID: 25356972), as well as in 0/1005 cases and 5/23705 controls in a pancreatic cancer case-control study (PMID: 32980694). This variant has been identified in 7/282896 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sema4, Sema4	RCV000572967	SCV002530713	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-02	criteria provided, single submitter	curation
Baylor Genetics	RCV000549911	SCV004202017	uncertain significance	Familial cancer of breast	2023-11-07	criteria provided, single submitter	clinical testing
GeneDx	RCV004592565	SCV005078796	uncertain significance	not provided	2024-02-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with breast, uterine, or familial pancreatic cancer, but also present in unaffected controls (PMID: 25356972, 30287823, 33471991, 26689913); This variant is associated with the following publications: (PMID: 25356972, 28726808, 24485656, 20871615, 19609323, 30287823, 33471991, 32980694, 26689913, 36243179)
Leiden Open Variation Database	RCV001030336	SCV001193270	uncertain significance	Pancreatic cancer, susceptibility to, 3	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Yukihide Momozawa.